TWI342307B - Propane-1,3-dione derivative or salt thereof - Google Patents

Description

(1) (1) 1342307 IX. Description of the Invention [Technical Field of the Invention] The present invention relates to a novel propane-1,3-dione which can be used as a medicament, particularly as a therapeutic agent for a gonadal-related disease. [Prior Art] It is known that hypothalamic hormone or pituitary hormone is involved in the secretion of a mechanism for controlling peripheral hormones. Usually, the secretion of anterior pituitary hormone is controlled by peripheral hormone secretion secreted by the upper central hypothalamus, which is secreted by accelerating hormones or secreting inhibitory hormones or from organs of individual hormones. Gonadotropin-releasing hormone (hereinafter referred to as GnRH, GnRH, also known as luteinizing hormone-releasing hormone; LHRH) is known as the highest-order hormone that controls the secretion of gonadotropin, via a receptor present in the anterior pituitary (hereinafter also referred to as GnRH). Receptor) Controls the secretion of the anterior pituitary hormone luteinizing hormone (hereinafter also referred to as LH) and follicle stimulating hormone (hereinafter referred to as FSH) and gonadal hormone in the gonads (Hormone Th Rinsho (Hormone and Clinics) Spring Special Issue 46, 46- 57 (1998)). Because this specific and selective antagonist of GnRH receptor regulates the action of GnRH and controls the secretion of accessory LH and FS and gonadotropins, it is predicted to be a prophylactic or therapeutic agent for gonadal hormone-dependent diseases (Horbon and Clinics Spring Special (1998)). Currently, the peptide compound cetarere (cetr 〇re 1 i X) (Non-patent Reference 1) and Abirey (abare 1 ix) (Non-patent Reference 2) are available as GnRH receptor inhibitors. . -5- (2) (2) 1342307 On the other hand, as a non-peptide compound having GnRH receptor antagonisticity, the thienopyrimidine derivative ΤΑΚ-0 13 (Non-Patent Reference 3) and the uracil derivative NBI- 42902 (Non-patent Reference 4) is now undergoing clinical trials. In addition, Patent Reference 1 reveals that propane-1,3-dione derivatives have GnRH receptor antagonism

(wherein 'A and B' may be the same or different from each other, and each represents a substitutable aryl group or a substituted heteroaryl group. For details, see the aforementioned publication). However, there is no description of a compound having a hydrazine-hydroxyalkyl substituent in ring A or ring B. [Non-Patent Reference 1] Proc Natl. Acad. Sci., USA, 85, 1637-1641, 1988 [ Non-patent reference 2] J. Urol., 167, 1670-1 674, 2002 [Non-patent reference 3] j. Clin. Endocrino 丨. Metab., 88, 1697-1704, 2003 [Non-patent reference 4] J. Med. Chem., 2005, 48, 1169-1178 [Patent Reference 1] International Publication W〇02/02533 (3) 1342307 [Disclosure of the Invention] [Problems to be Solved by the Invention] The object of the present invention is to provide An agent that produces superior GnRH receptor antagonists in vivo, especially a novel compound that can be used as a therapeutic agent for prostate cancer, prostatic hypertrophy, and the like. [Method for Solving the Problem] The present invention tests a propane-1,3-dione derivative, and the result is determined to be propane-1 having 2-(1,3-dihydro-2H-benzimidazol-2-yl). A 3-diketone or a compound having a benzene or a quinone ring substituted with a group derived from a 1-base group, in addition to excellent GnRH receptor antagonism, also exhibits excellent blood movement ability by oral administration, Thus the present invention has been completed. Namely, the present invention relates to a propane-1,3-dione derivative represented by the formula (I) or a salt thereof. It is also a drug which uses the compound as an active ingredient, especially a GnRH receptor antagonist.

(8)23〇7

The "lower courtyard" is a linear or branched chain saturated C 1.6 hospital base, which is more methyl, ethyl, isopropyl, hexyl or the like. "Low-extension alkyl" is a straight-chain and branched-chain saturated C, .6 stretching base, which is intended to be methyl-extended, extended isopropyl or the like. The "substitutable benzene" and the "substituted pyridine" are a benzene ring or a pyridine ring which may be substituted by a substituent, wherein the substituent is _CN, a halogen group which may be substituted by halogen, -〇 _low alkyl, _c 〇 〇 但 or aryl, preferably halogen or lower halogen group substituted by halogen. 6 "Substitutable imidazolyl" is one or two substituents φ As the imidazolyl group, a lower alkyl group is desirably used as a substituent. "Substitutable dioxolane" is a dioxolane which may be substituted with 1 or 2 substituents, preferably a lower alkyl group, a lower alkenyl group, a-0-low alkyl group or a methoxy group-low alkyl group. Substituent. "Substitutable lower alkyl" is a lower alkyl group which may be substituted with 1 or 2 substituents, and is desirably substituted with an amine group or a mono- or di-low alkyl amine group. The base is a lower alkyl group which may have 1 or 2 substituents, and may be exemplified by 〇H, COOH, -CO-O-low alkyl 'CN, phenyl, -0-low alkyl, -0 -C0-lower alkyl, amine, mono-lower alkylamino, -C0-NH2, -CO-mono- or di-loweramino group; g group is a preferred substituent. "Cycloalkyl" means a C3-6 monocyclic saturated hydrocarbon ring group, preferably a decyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. "Cycloalkanediyl" means that the divalent group of the C3_6 monocyclic saturated hydrocarbon ring is a cyclopropanediyl group, a cyclobutanediyl 'cyclopentanediyl group, a ring phase to three elements, an alkyl group. [Substituting ί for the replacement of ruthenium [based on the basis. i is substituted for alizarin, or di-: ring 丨 丙 1, 1, compared to L alkane -12-(9) (9) 1342307 or the like, of which cyclopropanediyl is particularly desirable. "Blood mobility" means that the orally administered pharmaceutical agent is absorbed by the digestive tract, produces an initial liver-passing effect, and then enters the blood. A compound in which a hydroxyl group is replaced by a prodrug forming group is also included in the compound of the present invention. Examples of prodrug-forming agents include Hiroshi's Grace ' 5 ' 2157- 2 1 6 1 (1 9 8 5 ) and ^ Iyakuhin no Kaihatsu (Development of Medicaments) " V o 1.7 (H i r o k a w a Shoten , 1 990) Bunshi

The group described by Sekkei (Molecular Design), pp. 163-198. The compounds of the invention possess tautomers. For example, described below.

Isolated forms of such isomers or mixtures thereof are also included in the invention. Moreover, the compounds of the present invention may have asymmetric atoms or axial asymmetry depending on the type of substituent, and thus may exist based on asymmetric atoms or their like. Mixtures of such optical isomers and their isolated forms are also included in the present invention - 13-(10) 1342307. Further, a compound in which the compound of the present invention is labeled with a radioactive isotope is also included in the present invention. Further, the compound of the present invention has a compound in which the geometrical isomerism of the 2-position double bond of propane can be mutually converted via tautomerization as described above. The examples are shown below.

Further, the compound of the present invention sometimes forms an acid addition salt or forms a salt with a base depending on the type of the substituent, and such a salt is included in the present invention, and its limitation is that it is a pharmaceutically acceptable salt. Examples include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and its like inorganic acids or with formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid. Butyric acid 'lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethyl acetate, p-toluenesulfonic acid, aspartic acid, glutamic acid and acid-addition salts formed by organic acids' Sodium, potassium, magnesium, calcium, aluminum and their inorganic bases or salts with methylamine, ethylamine 'ethanolamine, lysine, ornithine and their organic salts, ammonium salts and the like. The various hydrates, solvates and polymorphic substances of the compounds of the present invention and their pharmaceutically acceptable salts are also included in the present invention. -14 - (11) (11) 1342307 (Manufacturing method) The compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by various conventional synthetic methods using characteristics based on the type of the basic ring or substituent. In some cases, depending on the type of functional group, the functional group can be replaced at the stage of the starting material to the intermediate using a suitable protecting group (a group which can be easily converted into the functional group). Examples of such a functional group include an amino group, a thiol group, and the like, and are described by Greene and Wuts, "Protective Groups in Organic Synthesis, Third Edition" (JOHN WILEY & SONS, 1991). The protecting group and the like may be an example of a protecting group which may be optionally selected depending on the reaction conditions, by which the reaction may be carried out after the introduction of the protecting group, and then the protecting group may be removed as the case may be. The compounds of the present invention are generally described below. In this connection, the production method of the present invention is not limited to the examples described below. The abbreviations in the following sentences are as follows: DMF: N,N-dimethylformamidine Amine; DMSO: dimethyl sulphate; THF: tetrahydrofuran; τ〇ι: toluene; DCE .1, 2 - qi scholastic: TEA: diethylamine; Diglyme: di(ethylene glycol) dimethyl ether ;LiTMP: lithium 2,2,6,6-tetramethyl-7-aminobutyrate; LDA: lithium diisopropylamide; WSCHC1: 3-(3-dimethylaminopropyl)-1 -ethylcarbodiimide hydrochloride; HOBt: 1-hydroxybenzotriazole; CDI: 1,1'-carbonyldiimidazole. -15- (12) 丄增〇3〇7 Method of manufacturing a method of manufacturing

(The symbols in the reaction scheme are as follows: R: lower alkyl group, R 1 , R2, R 1Q1, R 1Q2, R 1 G3 and r 1 Q4 may be protected by a φ protecting group, as described below). This production method is a method for producing the compound (I) of the present invention. A 2-methylimidazole compound (ill) obtained from the 1,2-diaminobenzene compound (II) by a method based on the production method 4 described in Patent Reference 1, which is a compound (fluorene) and a mercapto compound. (IV) The reaction mixture is treated at room temperature or under heating in the presence of morphine or an organic base thereof in a reaction inert solvent to obtain an imidazole compound (VI). Such a mercapto compound (IV) can be present, for example, in the presence of DMF or a catalyst thereof in the presence or absence of -16 - 1342307 by means of methylene chloride or a solvent inert to the reaction, at room temperature or under heating. Next, it is obtained by chlorinating the corresponding carboxylic acid compound using sulfinium chloride, grass ugly chlorine or a chlorinating agent thereof. Sulfosulfonium chloride or the like can be used directly as a solvent. The resulting reaction mixture can be purified by azeotropy treatment with T〇1 or its like, with or without further purification. In addition, it can be separated or not separated from the intermediate (V) and its kind. Secondly, the intermediate compound (VI) and the mercapto compound (VII) can be reacted in the presence of TEA or a base thereof in the presence of TEA or a base thereof in a reaction solvent of Diglyme or the like to prepare an intermediate. The compound (Villa) and its kind are then prepared by adding a carboxylic acid (Vila) corresponding to the compound (Villa) or reacting a corresponding amount of water, and heating the mixture to obtain the compound (I) of the present invention. The mercapto compound (VII) can be obtained by a method similar to the preparation of the compound (IV). In addition, it may be isolated or not separated from the intermediate (VIIIa) and its class. Second manufacturing method

Compound (V" Step 4 (According to Method 1), Step 3 Chlorination

R1. : R. -17- (14) 1342307 This method of manufacture is particularly suitable for the preparation of the compounds of the invention (丨3) and (Ia-i). The optically active compound of the present invention can be selectively produced by using the optically active compound (Vlld) and (Vile) as a raw material compound by such a production method. Step 1: This step is a conventional method for protecting 1,2 or 1,3 -dihydroxy compounds. The protecting groups and their likes described in "Protective Groups in Organic Synthesis (3rd Edition) g (JOHN WILEY & SONS, 1991), edited by Greene and Wuts, are selected and used depending on the reaction conditions. In this case, when the optically active 1,2-dihydroxy compound (VI Id) and the (Vile)-substituted compound (Vllb) are used as the starting materials, the compound (V 11 d ) and V II e ). (1): This step is a conventionally known method for Stille coupling reaction (for example, J.K. Stille et al., J. Org. Chem., 52, 422-424, 1987). More specifically, this can be achieved by the presence of tris(dibenzylideneacetone) dipalladium or its palladium catalyst and tris-tert-butylphosphine or its phosphine-like compound at room temperature or under heating. Also preferred in the argon atmosphere is a halogenated aryl compound or an aryl triflate compound (preferably a bromoaryl compound (XI) or an iodonium compound), and a corresponding amount of tributyl (vinyl) The tin or its organotin reagent is reacted in T〇1 or a reaction inert solvent thereof. (2) This step is a conventional method of asymmetrically dihydroxylation of an olefin compound (χΙΙ). For example, 'this is done by the method described in the reference "Sharpless, κ Β. et al., Chem. Rev., 94, 1994, 2482-2547", for example, in a third butanol-water mixed solvent or its reaction inertia. In the solvent, oxidation of the olefin compound was carried out using AD-mix (AldriCh, USA). The reaction system -18-(15)1342307 is carried out at a temperature from ice cooling to heating, preferably to room temperature. The optically active 1,2-dihydroxy compounds (Vlld) and (Vile) having the desired absolute configuration can be prepared by appropriately using AD-mix-α and AD_mix-yS. See the chemical reaction scheme below.

Step 2: This step is a conventional hydrolysis reaction carried out in the presence of sodium hydroxide or its like inorganic base in a reaction solvent of THF, methanol or the like at room temperature. Step 3: This step is carried out by a customary method (K G Akamanchi et al.*

Synlett, 1 999, 11, 1 763 - 1 78 5). For example, a mercapto chloride former is prepared from methanesulfonium chloride and 1H-benzotriazine in methylene chloride or a reactive inert solvent thereof, and the mercapto compound (X) is cooled by ice, at room temperature or The reagent is prepared by reacting the reagent with a corresponding carboxylic acid compound (IX) dissolved in dichloromethane or a reactive inert solvent thereof. The obtained compound (X) can be purified by azeotropy treatment with Tol or the like, and may or may not be further purified. Step 4: This step is carried out according to the first manufacturing method. Step 5: This step is the acetal -19-(16) 1342307 of the 2,1 or 1,3-dihydroxy compound.

The protected compound (I b- i) is subjected to a conventional deprotection reaction to produce a dihydroxy compound (Ia-i). This method can be carried out under the reaction conditions and the conditions described in "Protective Groups in Organic Synthesis (3rd Edition)" by Greene and Wuts (JOHN WILEY & SONS, 1991). In addition, when an olefin compound (XII) The vinyl group is like 2-vinyl-2-fluorobenzyl acid in the ortho position of the fluorine atom or in the ortho position of the substituent having the force of the clamping force. The aryl metal compound is introduced. For example, an aryl metal can also be prepared by treating 2-ethyl fluorobenzyl acid with LiTMP, LDA or an organometallic base thereof in a THF or a reactive inert solvent thereof at a low temperature, preferably at -78 ° C. a compound, which is then reacted with a compound derived from DMF or a methylidene-based compound at a low temperature (preferably -78 ° C) to obtain ethyl 3-methylindol-2-fluorobenzylate, followed by The conventional Wittig reaction converts a fluorenyl group into a vinyl group to synthesize. In detail, the Wittig reaction is carried out in a reaction inert solvent such as THF or its like, φ in sodium hydride, alkyl hydrazine, potassium t-butoxide or In the presence of a base, it is preferred to carry out the reaction of the aldehyde compound with a corresponding amount of the hydrazine salt in an argon atmosphere at a temperature of from ice to room temperature. -20- 07) 1342307 Third manufacturing method

R*R9C(OR)j

(In the reaction scheme, Ra and Rb may be the same or different from each other, and each represents H or a lower alkyl group, CH2NMe2, CH2〇Me, CN, Ph, c 〇2 E t, c F; or a cycloalkyl group, Or Ra and Rb may together form a cycloalkyl group, and Rc represents H or a lower alkyl group. The compound (VI) prepared from the first method and the brewing compound (XIII) can be converted into a compound by a method for dihydroxylation of a hydrocarbon compound by a conventional method. (Ia_iii) (edited by J March)

ADVANCED ORGANIC CHEMISTRY" (JOHN WILEY & SONS, 992). This reaction is better in the presence of N-methylmorpholine, heart oxide or a co-oxidant thereof, in THF-water or its like In the reaction inert solvent, the oxidation of the olefin compound is carried out by using tetraoxide to oxidize. The reaction is carried out by cooling to ice at a temperature of ice, preferably at room temperature. Compound as a 1,2-dihydroxy compound (I a _丨i) can be converted into a ketal compound (Ib-ii) or an orthoester compound by a conventional method using a compound equivalent to a ketone or an orthoester compound. These can be regarded as ^2_dihydroxy compound-21- (18) (18) 1342307 Protection reaction 'and can be carried out using the aforementioned 'Protective Groups in. Synthesis (3rd edition), the reaction conditions and conditions thereof. The fourth manufacturing method

(The symbols in the reaction flow chart are as follows. Fantasy: Halogen or its class is decoupled,

Nu : Ketone or,

Rd : a substituent corresponding to X in the general formula (1) on a low alkylene group, and R201: ·5(0)ιη - low-based, -N3, N(R6)R, ·0(:〇 - Low-grade base or halogen-22-(19) 1342307. The same is true. This production method is a method of producing a compound having the above-mentioned group as the compound R2 in the compound (I) of the present invention. This method of manufacture is carried out by using THF, acetone, DMF, acetonitrile, di-methane methane, methanol, DM SO or a reactive inert solvent thereof, if necessary, in the presence of potassium carbonate or its inorganic base or TEA or its organic base. The nucleophilic reagent having the detachment group L12 compound φ (XV) (converted from the compound (VI) according to the first production method) and the corresponding amount of the reaction is carried out under cooling, from room temperature to heating or under reflux. The SN2 type substitution reaction is carried out. The nucleophilic § formulae can be exemplified by potassium acetate, sodium azide, sodium thiomethoxide and an anion-like compound thereof or an amine compound and a basic compound thereof, chloride ion and the like. When Y in the compound (XV) is a ketone, the ketone compound (XVII) converted from the compound (V) according to the first production method can be reacted with bromine or hydrogen bromide in acetic acid or a reactive inert solvent thereof. The above-mentioned Sn2-type substitution reaction can be carried out on the compound (XVIII) by conversion to the α-bromo ketone compound φ (XVIII). The resulting substituted compound can be converted to (I.i) by reduction of the ketone by a reduction reaction as shown below. When the nucleophilic reagent is an S-low alkyl group, the thiol group of the obtained compound can be converted into an anthraquinone compound or an anthracene compound by using an oxidizing agent according to the first production method of Patent Reference 1. As the oxidizing agent, it is more preferable to use m-chloroperbenzyl acid or hydrogen peroxide. -23- (20) 1342307

Fifth manufacturing method

(In the reaction scheme, X2 represents a halogen, and ring D represents a pyridine or imidazole which may be substituted). The production method is the hydroxy compound (XIX) in which the hydroxy compound (Ι-ii) is reacted in an inert solvent of THF or its reaction at a temperature of from -7 to 8 ° C to room temperature. It is prepared by reacting an organolithium compound (XXI) prepared from a nitrogen-containing halogenated aryl compound (XX) using n-butyllithium or an organic base thereof. The sixth manufacturing method is a method in which a dithioacetal compound (ΧΧΠ) and a diamine compound (XXIII) are heated in a reaction solvent of BtOH or the like at room temperature or under heating (preferably under reflux). The condensation reaction is carried out. -24- 1342307

(In the reaction scheme, R111 and R112 represent a lower alkyl group, or R111 and R112 may together form a ring, and the substituent on ring B may be protected with a suitable protecting group). Further, the compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by a conventional substituent conversion method using a feature based on the type of the substituent. 1. Reduction reaction The reduction of a ketone to a hydroxyl group, the reduction of an azide group to an amine group, the reduction of an unsaturated alkyl group to a saturated alkyl group, and the like can be carried out according to the fourth production method of Patent Reference 1. Examples of more desirable methods include a method in which sodium borohydride, lithium borohydride, diisobutylaluminum hydride, lithium aluminum hydride or a reducing agent thereof is used, and palladium (Pd), platinum (Pt), nickel is used therein. A method of catalytic reduction of (Ni) or the like in the atmosphere of hydrogen or ammonium formate or a hydrogen-like donor thereof. 2. Hydroxyl or amine group oximation reaction hydroxy or amine group oximation reaction in dichloromethane, DCE, pyridin, THF, Tol or a reactive inert solvent thereof, in dimethylaminopyridyl or -25- (22) 1342307 The presence or absence of a hydroxy compound or an amine compound is carried out by reacting a corresponding amount of a mercapto chloride compound or an acid anhydride at room temperature or under heating. Or in DMF or its reaction-inert solvent, in the presence or absence of WSHC1, HOBt, CDI or its like condensing agent, dimethylamino D ratio b or its reaction accelerator and TEA or its organic base In the presence of the hydroxy compound and the corresponding amount of the carboxylic acid compound, the reaction is carried out at room temperature or under heating. When two or more hydroxyl groups are present, the reaction can also be carried out selectively at the desired position by using a protecting group as appropriate. The dihydroxy compound can also be converted into a cyclic carbonic acid compound (cyclic carbonate compound) by using CDI or the like. In the case of a compound having two or more hydroxyl groups and an amine group, it may be acidified or partially deuterated. 3. Hydrolysis reaction The reaction of hydrolyzing an ester compound into a hydroxy compound and a carboxylic acid compound can be carried out in accordance with the eighth production method of Patent Reference 1. As a more preferred method, φ is carried out in THF using sodium hydroxide, potassium hydroxide or a base thereof. Conversion of 4.1,2-dihydroxy compound to aldehyde compound The reaction of converting a 1,2-dihydroxy compound into an aldehyde compound is carried out by using iodine or a salt thereof in a reaction inert solvent of THF, water, methanol or the like. Lead tetraacetate or an oxidizing agent thereof is carried out by oxidative cleavage of 1,2-dihydroxyethyl group. The obtained aldehyde compound can be converted into an amine compound according to the fifth production method of Patent Reference 1, in methylene chloride or a reactive inert solvent thereof. -26 - (23) 1342307 The compounds of the present invention can be isolated and purified as free compounds, pharmaceutically acceptable salts, hydrates, solvates or polymorphs thereof. The pharmaceutically acceptable salt of the compound (I) of the present invention can also be obtained by a salt formation reaction which is generally used. Isolation and purification are carried out using general chemical manipulations such as extraction, fractional crystallization, various types of separation chromatography, and the like. The various isomers can be separated by selecting an appropriate starting compound or by utilizing the difference in physicochemical Φ properties between the isomers. For example, by selecting an appropriate starting material or by isolating the racemic compound (for example, using a general optically active base or acid to convert it into a non-image isomer, followed by optical resolution, or using a palm The method of separating the column or its kind), converting the optical isomer into a pure chemical isomer. In addition to the compounds of the examples described below, the compounds in the following table can be obtained in the same manner as in the production method of the present invention. The active ingredient of the present invention and the compound of the present invention or a pharmaceutically acceptable Φ salt thereof may be used alone as a pharmaceutical agent, but it is usually used from one or two or more active ingredients 'using a pharmaceutical carrier, a tanning material and similar materials generally used in the field. It is prepared by the usual method. The administration can be oral administration using a tablet, nine doses, capsules, granules, powders, solutions and the like, or for intra-articular, intravenous, intramuscular and intra-articular injections, suppositories, eye drops, and eyes. Oral administration of ointments, transdermal solutions, ointments, transdermal patches, transmucosal solutions, transmucosal dressings, inhalants, and the like. The solid composition for oral administration of the present invention uses a tablet, a powder, a granule, and the like. In the solid composition, one or more active ingredients of -27-(24)(24)1342307 and at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, Polyvinylpyrrolidone and/or aluminum magnesium citrate are mixed. Generally, the composition may contain other additives than inert diluents such as magnesium stearate or a lubricant thereof, calcium cellulose glycolate or a disintegrating agent thereof, a stabilizer, and a dissolution aid. Lozenges or nine doses may be coated with a sugar coating or a film of stomach or intestinal material, such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like, as needed. . The liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and contains an inert diluent which is generally used, such as pure water or ethanol. In addition to the inert diluent, the composition may also contain a solubilizing agent, a wetting agent, a suspending agent and an adjuvant thereof, as well as a sweetener, a flavoring agent, a flavoring agent and a preservative. Parenteral injections include antiseptic aqueous or non-aqueous solutions, suspensions and emulsions. Examples of diluents for use in aqueous solutions and suspensions include distilled water for injection and physiological saline. Examples of the diluent used in the nonaqueous solution and the suspension include propylene glycol, polyethylene glycol, olive oil or a vegetable oil thereof, ethanol or its alcohol, 'P〇丨ysorbate 80 (trade name) and the like. The composition may further comprise an tonicity agent, a preservative, a wetting agent, an emulsifier, a dispersing agent, a stabilizer or a dissolution aid. It can be filtered, for example, by a bacteria retention filter, by blending a bactericide or by radiation sterilization. Alternatively, it may be used by dissolving it in sterile water for injection or a sterile solvent before use. Mucosal preparations such as nasal preparations can be used in solid, liquid or semi-solid form -28 - (25) 1342307 state and can be prepared by conventional methods. A conventional pH adjusting agent, preservative, thickening agent and dip is added as appropriate, and is formed into a solid, liquid or semi-solid state. The nasal preparation is administered using a general nebulizer, a nasal drop container, a tube, a nasal insertion tool or the like. The right is administered orally, and the appropriate daily dose is usually about 〇. 〇〇I to 1 〇〇mg/kg' is preferably 0.1 to 30 mg/kg, more preferably 0.1 to 1 mg/kg, and this The dosage is administered in single or divided doses into two or more doses. φ In the case of intravenous administration, a suitable daily dose is about 0.000 1 to 10 mg 7 kg body weight, which is administered once daily or divided into two or more doses. Further, the transmucosal formulation is administered once daily or divided into two or more doses at a dose of from about 0.001 to 100 mg/kg body weight. This dose is determined by considering the symptoms, age, sex, and the like in each case. [Examples] Hereinafter, the present invention will be described in further detail based on examples. The compound Φ of the present invention is not limited to the compounds described in the following examples. Further, the production method of the raw material compound is shown in the reference example. In this connection, the abbreviations in the specification are as follows. FA : FAB-MS(M + H)+ ; FN FAB - MS (Μ - Η) ; FAB - MS is a measurement of fast atomic impact ionization mass spectrometry; ES + is ESI+; ES - is ESI-; El: EI-MS; EI-MS is a measurement of atomic impact ionization mass spectrometry; N1: NMR characteristic peak 5 ppm (DMSO-d6, TMS internal standard); N2: NMR special microwave peak < 5 ppm (CDCl3 'TMS internal standard'; brs: wide single peak; mp: melting point: [a] D: -29- at 26 ° C (26) 1342307 rotation angle (c: concentration (gram solute / 1 〇〇 cm3)] VIe〇H: measuring solvent); CN or NC: cyano; vin: vinyl; ph: phenyl; Me: methyl; diMe: dimethyl: Et: ethyl; iPr: isopropyl; Propyl; cBu: cyclobutyl; nBu: butyl: cHex: cyclohexyl; Ac: ethyl hydrazide; diCl: dichloro; diF: difluoro; triF: trifluoro: diOH: dihydroxy: Py: 13 pyridine Py3: pyridin-3-yl; Py4: pyridin-4-yl; Py5: pyridyl-5-yl; dixr4: dioxol-4-yl; Thiop: thiophene; Thiop2, : thiophen-2-yl Thiop3: thiophen-3-yl; pheny: phenyl group: oxal: oxalate: ReX: reference example; Rex No.: Reference example number: Ex: Example; Ex No.: Example No.; RATA: Reference Example 1 and physical properties - 1-based compound of a known compound. Reference Example 1-2 - 4.0 g of 2-methyl-1H-benzimidazole and 13.9 ml of TEA were dissolved in 40 ml of Diglyme, to which 17.5 g of 2-chlorobenzylhydrazine chloride φ reaction mixture was added dropwise. Stir at 〇〇 ° C for 3 hours. After cooling to room temperature, the reaction mixture was combined with water, extracted with chloroform, dried over anhydrous sodium sulfate, and then concentrated to give an orange oil. This material was dissolved in 60 ml of methanol, mixed with 7.9 ml of oxaline, and then heated under reflux for 3.5 hours. The reaction mixture was cooled to room temperature and mixed with water, followed by stirring for 1 hour. The formed precipitate was collected by filtration and washed with cold water, followed by drying to obtain 6.1 g (75%) of 1-(2-chlorophenyl)-2-(1,3-dihydro-2^benzimidazole- A pale yellow powdery crystal of 2-yl)ethanone (Reference Example 1-2). E S + : 2 7 1. The compounds shown in Tables 5 and 6 were prepared in the same manner. -30- (27) 1342307 Table 5

Rex No. R101 R1® R»1 RSE R® Data Rex Να Rm Furnace Data 1-1 Η Η 3*f SF HP, 知 1-24 HH & Sr H FA;335:333(1:1) 1- 2 Η Η 2-α HH ES+: 271 1-25 HH 3-F & a H FA; 289 1-3 Η Η 2-FHH FA: 255 1-26 HH 44= H FA; 269 • Μ Η Η 2 -Me HH ES+251 1-27 HH 20 5-FH Unpurified 1-5 Η Η HH FA: 255 1-28 HH ser 4-FH FA:335:333(1:1) 1-6 Η Η SCN HH ES+262 1-29 HH 30 4Cl H Not purified 1-7 Η Η 3^VleO HH ES+:567 1-30 HH 2-F 3*FH FA: 273 1-β Η Η SMe HH ES+251 1-31 HH 2-f H ES+273 1-9 Η Η SO HH ES+1271,273 1-32 HH 3-F 4-FH FA: 273 1-10 Η Η 3-MeOCO HH N1:3.91(3H, S) , 6.08(1 H,s) 1-33 HH sa 5-a H FA: 305 1-11 Η Η 3-vinyl HH FA: 263 1-34 HH 3^F 5-CFs H FA; 323 1-12 Η Η HH ES+255 1-35 HH 2-F 5·Ρ Unpurified 1-13 Η Η 40 HH ES+271f273 1-36 HH SF FA: 291 1-14 Η Η 4-Me HH ES+251 1- 37 FH 3-F 50 H ES+.307 1-15 Η ACH ACH HH FA262 1-38 FHHH FA: 273 1-16 Η Η scf3 H ES+: 323 1-39 FH On 5*FH FA291 1-17 Η Η 4 *0 H ES+: 289 1-40 FF &d H ES+:325 1-18 Η Η 2-Me 3-FH ES+569 1^41 FF SF &f H ES+:309 1-19 Η Η 2-MeO H ES+285 1 -42 FH 3-F &FH ES+:307 1-20 Η Η SMe 4-FH FA: 269 1^43 F a SCI H ES+:341 1-21 Η Η 2-Me 50 H FA: 285 1-44 F a SF Sf H ES+: 325 1-22 Η Η 2-Me SMe H ES+: 265 1-50 HH 3^r HH FA: 316314 (1:1) 1-23 Η Η 3-Me SMe H FA: 263

Table 6

Rex No. A ring data 1-45 2-CFrPy5 ES+: 306 1^6 Thfop2 ES+: 243 147 2-F-Py4 ES+: 256 1^8 2, ediaPy4 FA; 306 1-49 Thiop3 ES+: 243 Reference Example 2 -1 A portion of 3.8 g of chlorophyll chloride was slowly added dropwise to 30 ml of a dichloromethane solution containing 1.54 g of 3-vinyl benzylic acid and a catalytically effective amount of DMF at room temperature of -31 - (28) 1342307 The disturbance was carried out for about 2 hours, after which an appropriate amount of τ was poured into the mixture, and evaporation was carried out under reduced pressure to prepare 3-vinylbenzylhydrazine chloride. This material is dissolved in a small amount of Diglyme 'heated under 7〇〇c' and slowly added dropwise to 5 ml of 1-(3,5-difluorophenyl)-2- (1,3,2-difluorophenyl)-2- 1,3 -Dihydro-2H-benzoindole-2-yl)ethanone and 1.4 ml of TEA in Dig ly me solution. After the dropwise addition was completed, the person was heated to 100 ° C, heated for about 25 minutes, mixed with pure water, and then heated to 175 Torr, and heated for about 25 minutes. This was mixed with aq. sodium hydrogen carbonate aqueous solution, extracted with ethyl acetate several times, dried over anhydrous magnesium sulfate and then evaporated, and then the residue was purified by gel column chromatography from ethyl acetate-hexane (1:3) The extract obtained 0.83 g (Reference Example 2-1) (68%) 1-(3,5-difluorophenyl)_2-(1,3.dihydro-2^-benzimidazol-2-yl)-3 - Yellow-foamed compound of (3-vinylphenyl)propane-1,3-dione. FA: 403 ° The compounds shown in Tables 7 to 9 were obtained in the same manner.

-32- (29)1342307 Table 7 R501

Rex No. R501 Rsot R101 Data Rex No. R501 R32 R503 R101 R102 Data 2-1 3, SdiF HHH FA-403 2-22 3*Me 5-Me HHH ES+: 395 2-2 2-CI HHHH ES+: 401 2 -23 3^F 5-Br HHH FA: 465 2-3 2-FHHHH ES+: 385 2-24 HHH FA: 419 2-4 2-Me HHHH ES+: 381 2-25 30 4-FHHH FA: 419 2- 5 HHHH FA*385 2-26 2-CI 5-FHHH ES+: 419 2-6 3CN HHHH ES+: 392 2-27 SBr 4-FHHH ES+: 463 2-7 ^OMe HHHH FA: 397 2-28 30 4C1 HHH ES+: 435 2-8 3-Me HHHH ES+: 381 2-29 2-FHHH ES+: 403 2-9 3<3 HHHH ES+: 401 2-30 6-FHHH ES+: 403 2-10 3-MeOCO HHHH ES+: 425 2-31 SF 4-FHHH Not purified 2-11 Af HHHH ES+:385 2-32 SCI 50 HHH ES+: 435,437 2-12 4CI HHHH ES+: 401, 403 2-33 5CF3 HHH FA*453 2-13 A4Ae HHHH ES+:381 2-34 2-F 5~FHH ES+:421 2-14 A^CH HHHH ES+:392 2-35 4F 5>FHH FA:421 2-15 3CF3 4-FHHH ES+:453 2-36 34= 50 HFH ES+:437 2-16 3-F 40 HHH ES+:419 2-37 5-FHFH ES+:421 2-17 2-Me 3^= HHH ES+:399 2-38 3-F SCI HFF ES+:455 2 -18 2-MeO HHH ES+:415 2-39 Sf HFF ES+: 439 2-19 3-Me 4-FHHH ES+: 399 2-40 3-F & f H a H Not purified 2-20 2-Me 5<a HHH ES+: 415 2-41 3-F 50 HF a ES+: 471 2-21 2-Me SMe HHH ES+: 395 2-42 3-F 5-FHF a ES+; 455 Table 8

Rex No. A ring data 2-44 2-CF3-Py5 ES+:436 245 Thiop2 ES+:373 2-46 2-F-Py4 ES+:386 2-47 2,6<liCI-Py4 ES+:436 2-^8 Thiop3 ES+: 373

-33 - (30)1342307

Table 9

Rex No. R501 R502 R601- B Ring R-assisted R101 Data 2-49 FF 3-EtOCOCH=CH-Ph- HH FA:475 2-50 FH 3CICH2-Ph- HH FA:407 2-51 FF 3CICH2-Ph- HH FA: 425 2-52 FH 3-Ac-Ph- HH FN: 399 2-53 FF S-Ac-Ph- HH FA: 419 2-54 FF 5-Ac-Thiop2 HH FA: 425 2-55 FH 3- MeCH=CH-PI> 2-FH FA; 417 2-56 FF Φ-ΝΛη-Ph- HH ES+.403 2-57 FF 3-virvPh- H ES+:421 2-58 FF 4-vin-Ph- HF ES+ :421 2-59 FF 2-virvPh- HH ES+:403 2-eo FF 3-vin-Ph- 2-FH ES+:421 2-61 FF 3-vin-Ph- 4-FH ES+:421 2-62 FF 3-vin-Ph- 5*FH ES Ten: 421 2-63 HH 3-vin-Ph- HH ES+.367 2-64 FH 3-vin-Ph- 2-FH ES+: 403 2-65 FH 3-vin -Ph- 4-FH ES+: 403 2-66 FFHH ES+: 429 2-67 FHHH ES+: 411 2-68 FH 5-vin-Ph- 2,4·2 FH ES+: 421 Reference Example 3 Dissolved in 10 ml of ethanol A portion of 4.96 g of the original ethyl acetate was added to 50 ml of a solution of 4.68 g of 4-chloro-5-fluorobenzene-1,2-diamine in ethanol and heated under reflux for 4 hours. After the reaction liquid was concentrated, the residue formed was purified by silica gel column chromatography eluted from chloroform-methanol (1 0:1) to give 2.10 g (39%) of 5-chloro-6-fluoro-2-methyl- 1H-benzimidazole. ES+: 185. -34 - (31) 1342307 Reference Example 4 at -78. (:, 17.62 ml of 丨·59 M n-butyllithium·THF solution was added dropwise to 1 ml of a solution containing 4.73 ml of tetramethylhexahydro 13-pyridinium in THF. This material was at -i〇° c stir for 1 ' minutes 'cooled to -78 ° c 'mixed with 5.00 g of 2,4-difluorobenzyl acid tert-butyl ester dissolved in 20 ml of THF' and then stirred for 1 hour. After that, add 7.23 dropwise. The mixture was stirred for 1 hour, mixed with 5.34 ml of acetic acid, and then warmed to room temperature. This material was mixed with an appropriate amount of B pure water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated. Purification of 'self-alkane-ethyl acetate (20: 1-1 〇: 1) was purified by silica gel column chromatography to obtain 5.65 g (1%) of 2,4-difluoro-3-carboxylic acid. Tributyl ester. N2: 1.60 (9H, s), 7.04 (1H, m), 8.14 (1H, m), 10.38 (1 Η, s) Reference Examples 4-2 and 4-3 were prepared in the same manner. φ Reference Example 4-2 2-Fluoro-3-carboxybenzyl benzoic acid tert-butyl ester FA: 225 N2 : 1.62 (9H, s), 7.324 (1H, t, J = 8 Hz) ' 8.08 ( 2H,m) ' 1 0.42(1 Η * s) Reference Example 4-3 3-(2,2-Dimethyl-i,3-dioxol -4-yl)-2-fluorobenzaldehyde FA: 225 Reference Example 5 -35 - (32) 1342307 At -78 ° C, 9.50 ml of 1)-butyllithium-1'-machi solution was added dropwise to 90 ml It contained 8.13 g of iodinated methyltriphenyl scale in THF. This was stirred at 〇 ° C for 10 minutes, cooled to -78 ° C, and then mixed with 2.44 g of 2,4-difluoro-3-methylbenzylidene acid tert-butyl ester dissolved in 1 mL of THF. After 40 minutes, the mixture was stirred at room temperature for 1 hour, and mixed with aq. After concentration, the residue formed was purified by silica gel column chromatography eluting with hexane, ethyl acetate (50:1) to give 1.20 g (50%) of 2,4-difluoro-3-vinylbenzyl acid. Tributyl ester (Reference Example 5-1). ES-: 239. The following compounds of Reference Examples 5-2 to 5-5 and those shown in Table 10 were obtained in the same manner. Reference Example 5-2 2-Fluoro-3-prop-1-en-1-ylbenzyl acid tert-butyl ester EI : 236 φ Reference Example 5-3 3-(Cyclopropylmethyl)benzyl acid methyl ester FA : 189' Reference Example 5-4 2-Methoxy-3-ethylbenzoic acid methyl ester FA: 193, Reference Example 5-5 1-Dichloro-2-fluoro-3-ethyl phenylbenzene FA: 202. -36 - (33)1342307 Table 10

Rex No. R501 R Qiu FT Data S6 FH -CH=C(Me)2 FA; 413 5-7 FH -CH=CH{Me) FA; 399 5^8 FH -CH=CHCN FA: 410 5-9 FH -CH=CH-Ph ES+:461 5-10 FF -C(=CH2HVle not purified 5-11 FH -CH=CHHPr FA:427 5-12 FH -CH=CHCH2〇Me ES+:429 5-13 FF -CH =CHEt ES+:431 5-14 FH -CH=CHCH2N(Me)2 ES+:442 5-15 FH -CH=CH-cBu ES+:439 5-16 FF -CH=CH-cHex ES+:485 5-17 FH -CH=CH-cPr FA: 425 Reference Example 6 A portion of 4.27 ml of trifluoroacetic acid was added to 30 ml of a dichloromethane solution containing 1.33 g of 2,4-φ difluoro-3-vinylbenzyl acid tert-butyl ester. After stirring for 5 hours, after evaporating the solvent, an appropriate amount of pure water and a saturated aqueous solution of sodium hydrogencarbonate were added thereto, and the aqueous layer was washed with diethyl ether. The aqueous layer was adjusted to pH 1 with 1 HCl aqueous solution and extracted with diethyl ether. After drying over magnesium sulfate, 9 64 mg (95%) of 2,4-difluoro-3-vinylbenzyl acid (Reference Example 6-1) N2: 7.93 (m, 1H), 6.98 (m, 1H). ), 6.74 (dd, 1H, J = 12 Hz, 18 Hz), 6. 1 1 (dd, 1 H, J = 1 Hz, 1 8 Hz), 5.68 (dd, 1 H, J = lHz, 1 2 Hz) -37 - (34) 1342307 by the same 2-Fluoro-3-prop-1-en-1-ylbenzyl acid (Reference Example 6-2) was obtained (Frequent Example 6-2). FN 179. Reference Example 7 In the next 'will be 1. 〇μ hexamethylene sulphate - The THF solution was added dropwise to 10 ml of 300 mg of 3-2-(1,3-dihydro-2Η-benzoindole-2-yl)-3-(3-fluorophenyl)-3-yl Oxypropenyl)benzaldehyde and 69 mg of micro φ liter of acetone in THF' and stirred for 15 minutes. This was mixed with an appropriate amount of saturated aqueous solution of chlorohydrin and pure water, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After concentration, the residue formed was purified by a silica gel column, and 184 mg (53%) of 2-(l,3-dihydro-2H) was obtained from the mixture of ethyl acetate (2: 1:1: 2). -Benzimidazol-2-yl)-l-(3-fluorophenyl)-3-[3-(1-hydroxy-3-oxybutyl)phenyl]propane-l,3-dione (Reference example 7-1). ES+: 445 制According to the same way 'produced 1-{3-[2·(1,3-dihydro-2H-benzophenanthene-2-yl)_3-(3-fluorophenyl)- 3-Hydroxypropyl hydrazino]benzylidene 2-hydroxypropyl ester (Reference Example 7-2). ES+: 459. Reference Example 8 A 0.57 ml of bromine was slowly added dropwise to 80 ml of 4.18 g of fluorenyl-ethenylphenyl)-3_(3,5-difluorophenyl)_2·(,3·dihydro·2H_ sub A solution of benzimidin-2-yl)propane-oxime, 3-dione in acetic acid, followed by the addition of 5 ml of a 25% hydrogen bromide-acetic acid solution, and the mixture was stirred at room temperature for about 1 hour. The residue obtained by evaporation of the solvent under reduced pressure was combined with an aqueous solution of sodium bicarbonate water-38 - (35) 1342307 and extracted several times with ethyl acetate. - a bromoketone intermediate. This intermediate was dissolved in 50 ml of DMSO without purification, mixed with 2.16 g of potassium acetate, and stirred at room temperature for about 4 hours. The reaction mixture was mixed with aq. EtOAc (EtOAc) 1 : 2) Eluate to obtain 2.62 g (55%) of 2-{3-[3-(3,5-difluoro |phenyl)-2-(1,3-dihydro-2Η-benzimidazole) A greenish yellow foam of -2-yl)-3- oxypropenyl]phenyl}-2- oxyethyl ester. FA: 477. Reference Example 9 A 25 ml portion of a THF solution containing 7·8 g of tetrabutylammonium fluoride and 24 g of molecular sieve 4A was stirred at room temperature for 12 hours under an argon atmosphere. After cooling, 20 ml of 300 mg of 3·[2-(1,3·dihydro-2-indoleimidazolidin-2-yl)-3-(3-fluorophenyl)-3 was added dropwise thereto. - oxypropenyl]benzaldehyde φ and 1.7 g of diphenyl(2,2,2-trifluoroethyl)phosphine in THF. This was stirred at room temperature for 5 hours. The reaction mixture was filtered, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ % ) 2·(1,3-Dihydro-2Η-benzimidazole-2-yl)-1-(3-fluorophenyl)-3-{3-[(1Ζ)-3,3,3- Yellow powder of trifluoroprop-1-en-1-yl]phenyl}propane-1,3-dione. FA: 463. Reference Example 1 0 -39 - (36) 1342307 One ^^g of manganese dioxide is added to ^ml containing ^丨克! —(3,5-Difluorophenyl)_2-(1,3-dihydro-211-benzimidazol-2-yl)-3-[3-(hydroxymethyl)phenyl]propane-1, A solution of 3-dione in dichloromethane was stirred for 4.5 hours. After the calcium ore was filtered and concentrated, the resulting residue was crystallized from hexane-ethyl acetate to give y·09 g (52%) of 3-[3-(3,5-difluorophenyl)-2-(1, 3-Diargon-2H-benzimidazol-2-yl)-3-oxymethylindenyl]benzaldehyde (Reference Example 10-1). F A : 4 0 5. In the same way 'cracked 1_[3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-(fluorophenyl-indole-11-based propyl _ 1,3 -dione (Reference Example 10-2) FA : 344. Reference Example 1 1 part by weight 5.46 g of 3-(2,2-dimethyl-1,3·dioxolan-4-yl) Ethyl 2-fluorobenzylate was dissolved in 100 ml of THF and cooled to 0 ° C., then 40.8 ml of 1N aqueous sodium hydroxide solution was slowly added thereto. The mixture was warmed to room temperature and stirred for 17 hours. After THF, the residue was cooled to 0 ° C, and acetic acid was slowly added thereto until pH 値 became 3 to 4. This was extracted with diethyl ether, dried over sodium sulfate and concentrated, and then subjected to azeotropic treatment with Tol three times. 4.66 g (95%) of 3-(2,2-dimethyl-1,3.dioxolan-4-yl)-2-fluorobenzyl acid (Reference Example 1) was obtained. FN: 239. In the same manner, the compounds of Reference Examples 1 1 - 2 to 1 1 - 1 3 shown in Table 制 were prepared. In this connection, the compounds of Reference Examples 1 1 -6 to 1 1 - 1 2 were used as the corresponding optically active materials. -40 - (37) (37) 1342307 Reference Example 1 2 Add 35 mg of potassium acetate to 2 ml of 100 mg of 3-[3-(chloromethyl)benzene After a solution of -3-(3,5-difluorophenyl)-2-(1,3-dihydro-2Η-benzimidazole-2·yl)propane-1,3·dione in DMSO, the mixture Stir at room temperature for about 2 Torr. The reaction liquid was mixed with an appropriate amount of saturated aqueous ammonium chloride solution, extracted with ethyl acetate several times, dried over anhydrous magnesium sulfate and concentrated, and then the residue was purified by gel column chromatography. From the ethyl acetate-hexane (1:2) solution, 90 mg of a yellow oily material was obtained, which was crystallized from a small amount of ethyl acetate-hexane (1:3) to afford 68 mg (64%) ) 3-[3-(3,5·difluorophenyl)-2-(1,3-dihydro-2H-benzoimidazol-2-yl)-3-oxypropanyl]acetate; Yellow crystals of vinegar (Reference Example 12-1). FA: 449. In the same manner, 2-[2-(1,3-dihydro-2H-benzimidazol-2-yl)-3-acetate was obtained. (3-Fluorophenyl)-3-oxypropenyl]benzyl ester (Reference Example 12-2). FA: 43 1 Reference Example 1 3 parts 25 ml containing 1.2 g 3-{3-[3 -(3,5-difluorophenyl)-2-(l,3-dihydro-2H-benzimidazole-2.yl)·3-oxypropenyl]ethyl phenyl acrylate Cool down to _78 t in THF solution with argon Into this, 5.5 ml of a 1.0 Μ diisobutylaluminum hydride-Tol solution was gradually added dropwise, followed by stirring, and the mixture was stirred for about 2 hours. This material was again cooled to -78 ° C, and the same amount of reducing agent was added dropwise thereto, after which the mixture was gradually warmed to room temperature and stirred for about 40 minutes. The reaction liquid was cooled to -30 ° C or lower, a small amount of methanol and pure water were added thereto, and the formed non-41 - (38) (38) 1342307 dissolved matter was removed by washing with an appropriate amount of ethyl acetate. The organic layer obtained by the leaching operation was washed with water, dried over anhydrous magnesium sulfate and concentrated, and then the residue obtained was purified by column chromatography eluting from ethyl acetate-hexane (1:1). 0.58 g (53%) of 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-yl)-3-(3-hydroxypropan-1 Yellow foam of 1-en-1-yl)phenyl)propane·1,3·dione. FA: 43 3 〇 Reference Example 1 4 A portion of 104 mg of palladium acetate and 5 ml of TEA were added one by one to 50 ml of an acetonitrile solution containing 7.44 g of 3-iodobenzyl acid and 3.9 ml of ethyl acrylate. The mixture was sealed in a test tube and Heat for about 12 hours. After spontaneous cooling, the crystals were filtered, washed with ethyl acetate and ethyl acetate, and evaporated. The resulting crude crystals were recrystallized from a small amount of ethanol to give 5.82 g (yield: 88%) of white crystals of 3-(3- ethoxy-3- oxyprop-1- -1- yl) benzyl acid. FA: 221. Reference Example 1 5 -1 A portion of 1 g of 4-(3-bromophenyl)-2,2-dimethyl-1,3-dipropane was dissolved in 18 ml of THF solution and cooled to -78 t, then spent To this was added 2.35 ml of a hexane solution containing 1.57 m of n-butyllithium dropwise over 1 hour. After the dropwise addition, the material was stirred for another 30 minutes. After adding excessive amounts of carbon dioxide at -78 °C, the mixture was warmed to room temperature. The reaction solution was mixed with an aqueous solution of ammonium chloride, and extracted with chloroform-methanol (5:1) for 1 time. The organic layer was dried over sodium sulfate and concentrated, and then the residue was purified by gel column chromatography-42- (39) (39) 1342307 Retention (hexane: ethyl acetate = 1 : !) gave 550 mg (63%) of 3-(2,2-dimethyl-1,3-di-indole-4-yl)benzyl Acid (Reference Example 15-1). FA: 237. 2-butyl-3-(2,2-dimethyl) was prepared in the same manner from 4_(3·bromo-2-fluorophenyl)·2,2-dimethyl-1,3-dioxane 1,3-dioxane-4_yl)benzylic acid (Reference Example 15-2) (5%). F Ν : 2 7 7. Reference Example 1 6-1 A solution of 5.71 g of 3-[(lR)-l,2-dihydroxyethyl-2-ethyl fluorobenzylate dissolved in 30 ml of 2,2-dimethoxypropane, with 476 mg The p-toluenesulfonic acid monohydrate was mixed and stirred at room temperature for 3 minutes. This was mixed with a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. EtOAc was evaporated. =1 1〇: 1) Obtained 5.46 g (81%) of ethyl 3-[(4 R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-fluorobenzyl acid (Reference Example 16-1). FA: 269. In the same manner, the following optically active materials were used to prepare the optically active compounds of the following Reference Examples 1 6 to 9 and Reference Examples 16 to 8 using the corresponding optically active raw materials' from the reference examples 1 6 - 2 shown in Table 11. Reference Example 1 6-9(4R)-4-(3-Bromo-2-fluorophenyl)-2,2-dimethyl-1,3-oxylane FA: 2 76. Reference Example 1 7 A portion of 12.76 g of ethyl 3-bromo-2-fluoroacetate was dissolved in 5 ml of a T〇1 solution -43-(40) 1342307, and 15.8 ml of tributyl (vinyl) was added thereto in that order. Tin, 236 mg of tris(dibenzylideneacetone)dipalladium and 1.25 ml of tri-tert-butylphosphine 1% by weight hexane solution were stirred at room temperature for 13 hours under an argon atmosphere. This material was diluted with 300 ml of diethyl ether, mixed with 25 g of potassium fluoride, stirred for 30 minutes, and the insoluble material was filtered using a K i r i y a a funnel, after which the mother liquid was concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=40:1) to yield 10.3 g (97%) of ethyl 2-fluoro-3-vinylbenzyl acid (Res. 17-1). In the same manner, the reference compound 1 7 - 5 was obtained from Reference Example 1 7 - 2 shown in Table 11. Reference Example 1 8 -1 A 74.3 g portion of AD-mixyS was added to a mixed solvent of 265 ml of a third butanol and 265 ml of pure water, and dissolved therein at room temperature for 30 minutes. After cooling to 〇 ° C, this was mixed with K3 g of 2-fluoro-3-vinylbenzyl acid ethyl ester and stirred for 3.5 hours. This material was mixed with 79.6 g of sodium sulfite, and stirred at room temperature for 30 minutes, with The extract was extracted with EtOAc. EtOAc (EtOAc)EtOAc. 47%) ethyl 3-[(1R)-1,2-dihydroxyethyl]-2-fluorobenzylate (Reference Example 18-1). FA: 229 » In the same manner, as shown in Table 1 Reference Example 1 8-2 The following optically active compounds of Reference Example 18-8 and Reference Example 18-7 were obtained. Further, (1S)-1-phenylethane-1,2- was obtained by AD-mixa in the same manner. Glycol derivative. -44 - (41) 1342307 Reference Example 18-8 (lS)-ll-(3-bromo-2-fluorophenyl)ethane-1,2-diol FA: 236. Reference Example 1 9 A solution of 2.70 g of 3-bromo-2-chlorobenzyl acid in DMF (30 ml) was added with 1·1 ml of methyl iodide and 2.38 g of potassium carbonate at medium temperature, then 1 hour. The reaction liquid was mixed with water. After that, it is diluted with ethyl acetate. After the operation, the organic layer is sequentially water and saturated with salt. After washing, it was dried over anhydrous magnesium and then concentrated under reduced pressure. The obtained residue was purified by ethyl acetate-hexane (100:3) as solvent. Methyl 2-chlorobenzylate. FA : 250 » Reference Example 2 0 A solution of 0.72 ml of ruthenium-diisopropylamine in THF was cooled to room temperature -70 °C in an argon stream. 3.3 ml of hydrazine butyllithium-hexane solution was added dropwise, and then the reaction liquid was heated to about -15 ° C. The liquid was again cooled to about -7 (TC, mixed with 0.54 ml of 3-ethylpyridinium and stirred at the same temperature. After about 30 minutes, 5 ml of anhydrous THF containing 1.1 g of 3-((411)-2,2-dimethyl-1,3-dioxolan-3-yl)-2-fluorobenzaldehyde was slowly added thereto. Solution: After stirring at -7 (rC for about 20 minutes at about -3 Torr for about 3 hours, this is mixed with an appropriate amount of 0.2 Μ hydrochloric acid 'liquid' for extraction several times with ethyl acetate. The organic layer is saturated with water. Washing 'drying with anhydrous magnesium sulfate, then evaporating the solvent, forming a room-stirred layered sulfuric acid column to purify the anhydrous 1.54 reaction, dropping i -4- and water-soluble Residue -45- (42) (42) 1342307 The residue was separated and purified by chromatography on a silica gel column, yielding 0.77 g (45 °/.) from ethyl acetate-hexane (7:3). [3-((411)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2-fluorophenyl]-3-hydroxy-1-pyridin-3-yl-propane -1-ketone colorless oil. F A : 3 4 6. Reference Example 2 1 part 4 ml contains 0.38 g of 1-[3-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2.fluorophenyl]- 3-pyridin-3-ylpropane-1,3-dione and 1.3 g of potassium fluoride in DMF solution mixed with 0.1 g of carbon disulfide, stirred at room temperature under closed conditions for about 2 · 5 hours ' and 0 · 1 6 ml of methyl iodide was mixed and stirred under the same conditions for about 1 hour. The reaction liquid was mixed with an appropriate amount of pure water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue formed was purified and purified eluted eluted eluted eluted eluted eluted eluted eluted elution Methyl)-l-[3-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-fluorophenyl]-3-pyridine- Yellow oil of 3-ylpropane-1,3-dione. ES+: 448. -46 - (43)1342307

Table 1 1 〇 6 5 -702

Rex No. R邶FT R/UJ Data 11-2 Η 2-F 5-vin FN: 165 11-3 Η 2-f 3-vin FN: 165 11-4 Η 牟F S-vin FN: 165 11- 5 Η 3-F 5-vin FN: 165 11-6 Η 2 peach ^((2,2-rMe)-13-3(r4} ES-235 11-7 Η H 3^(2^-^Me) -1>^xr4} ES-221 11-β Η H ^(2,2-rMe)-1,3-i^r4) ES-221 11-9 Η 2-F , 3---30-4} FN239 11-10 Η M2,2-rMe)-1,Szxr4} FA241 11-11 Η 2-OMe ES-251 11-12 Η 2-0 M2^*zMe>1,3-z^r4} FA257 11- 13 Η H 3- —C=〇H FN:173 16-2 Et 2-Me ^(2^-zMeV1,3-3(r4} EI264 16-3 Me H 3^(2,2-1^)- 1 >=xr4) FA237 1&4 Me H 3^(2^-zMe>-1, Socr4} FA237 16-5 Β 2-FS{(2^zMe)-1,5-^0-4} FA269 1&6 a 4-F 3-f(2,2-zMe)-1,3-^xr4> FA269 16-7 Me 2*OMe FA267 Me 2-0 M22-=Me>-l,fcxr4> FA271 17 -1 Et 2-F 3-vin Day: 194 17-2 Et 4-f 3-vin FAi95 17-3 B 5*vin Day: 194 17-4 B 2-Me 3-vh N2; 7.44 (3K m) , 7.01〇K dd, J=11Hz, 17Hz), 5.59(1H dd, J=1Hz, 17Hz), 5.35(1Ht dd, J=1Hz. 11Hz), 4.36(2H q, J=7Hzl Z51(3H, s ), 1.39(3H, t, J=7Hz) 17-5 Me 2-a 3-vin FA197 1&-2 Et 2 Yao 3· HO N2: 7.42 (3H, m), 5.09 (^, m), 4.33(2H, q, J=7Hz) 158(4Ht m), 242(3K s), 157(3H, t J=7Hz) 1&3 Me H 3· HO N2£.00(2H, m ), 7.50(2H, m), 4.89(^, m> 352{3H, s) 3.73(2Η, m), Z87(1H, d, J=3Hz), 229(1K m) 1Μ Me H 3· HO N2fi.00(2H, m), 7.51(2Ht m), 4.89(1H, m), 332(3H, s) 3.73(2H m), 283(1H, dt J=3Hz), Z25(1H, m) 18-5 Et 4*f 3· HO FA229 Cut Me 2-OMe 3· HO FA227 18-7 Me 2-a 3-, Τ^^〇Η HO FA231 Example 1 -1 (1) By 5 ml Dichloromethane was added to a stirred solution of 0.80 ml of sulfinium chloride and 1.31 g of 1 Η-benzotriazole to prepare a mercapto chloride forming reagent -47 - (44) (44) 1342307. Thereafter, the previously prepared reagent was added to 90 ml of dichloromethane containing 1.96 g of (4 R)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)benzyl acid. Stir in the solution for 1 〇 at room temperature. After filtering the formed chloride, anhydrous magnesium sulfate was added to the filtrate, filtered and concentrated to give a mercapto chloride compound. (2) The mercapto chloride compound obtained in (1) was dissolved in 10 ml of Diglyme at 70 ° C, and added dropwise to 10 ml of 933 mg of 2-(1,3-dihydro-2H-phenylene). Imidazol-2-yl)-1-(3-fluorophenyl)ethanone and 1.28 ml of TEA in Diglyme solution. Thereafter, the material was heated to i〇〇°c, mixed with 66 μl of pure water, and then heated under reflux for 40 minutes. After cooling to room temperature, the material was mixed with an appropriate amount of purified water, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. After concentrating the organic layer, the residue formed was purified by silica gel column chromatography to obtain 1.68 g (100%) 2 -(1,3-hydrogen). · 2Η-Benzimidazol-2-yl)·Bu (3-[(4R)-2,2-dimethyl·1'3-dioxolan-4-yl]phenylindole_3-(( 3_Fluorophenyl)propane-, 3_dione (Example 1-1) In the same manner, the compound shown in Table 12 and Table 13 was prepared using the corresponding optically active substance. -48 - (45) 1342307 Table 12

Example No. R1U1 R401 Guard 1 R data 1-1 Η F 3-FH ES+: 459 1-2 Η 2-F 3-FH FA477 1-3 Η 2-F 3ΌΝ H FA: 484 1-4 Η 2-F 2-Me H FA;473 1-5 Η 2-F 3^Me H FA473 1-6 Η 2-F 2-CI H ES+:493 1-7 Η 2-F 2-FH FA477 1-β Η 2- FHH FA: 459 1-9 Η 2-F 3CI H FA-493 1-10 Η Η 3-FH Unpurified 1-11 Η 4-F 3-FH Unpurified 1-12 Η 2-Me 3-FH Not purified 1-13 F 2-F 3-FH unpurified 1-14 Η 2-F 3-MeO H unpurified 1-15 Η 4-F 3-F 5-F unpurified 1-16 Η 4-F 2-CI H not purified -49 - (46)1342307

f Example number R1. 1 R«n RSI R® A ring data V17 Η 2-nBu 3F H Ph FA*515 1-18 Η 4f HH Ph ES+: 419 1-19 Η 2-WeO H Ph FA-489 1- 20 Η 2-α Sf H Ph ES+: 493 1-21 Η 2-Μδ 3f SF Ph ES+: 491 1-22 Η 2-Me 30 H Ri K+: 489 1-23 Η 2-Me 2-QH Ph ES :489 1-24 Η 2-Me H Ph ES+:469 1-25 Η 2-Me HH Ph ES+:455 1-26 Η 2-Me 2-f H Ph ES+:473 1-27 Η 2-0 5f Ph ES+511 1-28 Η TrQ 30 H Ph E^509 1-29 FV3CH3〇2-F SF SF Ph FA6Q2 1-30 Η 4F 4a H Ph ESf:493 1-31 Η 2-Q 3-F 5f Ri N1 : 1.40 (64 m), 215 (3H, s) 4^9 (2K m), 5.17 (1H, [11), 7.03 (^^), 7.33⁄43⁄4.3⁄4^ Ηζ, δΗζ), 778 (2i, dt J=3Hz, 9Hz), 1350[2i brs) 1-32 Η 2-F 3f &F Ph FA495 1-33 Η 2-FHH Py3 FA.460 1-34 Η 20 2-d H Ph ES+509 1 -35 Η 20 HH Ph ES+:475 1-36 Η 2f H Ph ES+:493 1-37 Η 2-a SCN H Ph ES+500 1-38 Η 4f HH Ph ES+:459 1-39 Η 4F ^Me H Ph ES+: 473 1-40 Η 3Bf H Ph ES+539 Example 2 - 1 THF (12 ml)-pure water (3 ml) solution containing 72 mg of N-methylmorpholine-N-oxide With 〇.5 ml 〇.〇8 Μ4 Μ - a solution of the third butanol and 0.82 g of 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2Η-benzoindole-2-yl)-3-(3- Vinylphenyl)propane-13-dioxane was mixed and stirred at room temperature for -2 - (47) (47) 1342307 for about 2 hours. The hydrazine liquid was concentrated to a volume of about 1 M, mixed with an appropriate amount of an aqueous solution of sodium hydrogen sulfite, and extracted with ethyl acetate several times. The obtained organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated, and then the residue was purified by silica gel column chromatography to obtain s. 83 g (69 %) from chloroform-methanol (80:1). -(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazole-2-yl)-3-[3-(1,2-dihydroxyethyl)benzene Light-page crystallization of the base]propane-1,3-dione (Example 2_丨). In the same manner, the compounds shown in Tables 14 to 17 were obtained.

-51 - (48)1342307 Table 1 4

Example No. RW1 R1® R® Α Ring Data 2-1 Η Η ρ ρ,5·2 F*Ri FA437 2-2 Η Η Η FA487 2-3 Η Η Η 3aSf-Pt) =A453 2-4 Η Η Η 3,4,5·3 FPh FA 455, N1:328(^, m), 4.43(1K dd, J=4Hz, 6Ηή, 4.72(1K t, J=6Hz), 520(1^d J=4Hz) , 720 (8K m), 7.75 (24 m), 13.12 (2H, s). mp: 139-14 (fC 2*5 F Η Η 35. second-order FA455 26 FF Η Ρ·5·2 Ffh FA473 2- 7 Η Η Η 3f-Ph FA: 419 2 Η Η Η 3, & 2 pm OPh FA469 2-9 Η Η Η k 2 F*Ph pA437 2-10 Η Η Η FA470 2-11 Η Η Η 2β· II RPh FA437 2-12 F α Η 3 Ffh FA489 2-13 Η Η Η 4*F*Ph FM19 2-14 F Η Η p〇5f-Ph FA471 2-15 Η Η Η SMeOPh FA431 2-16 Η Η Η SC4f*Ph FA453 2-17 Η Η Η FA426 2-18 Η Η Η 38r-SF-fh FA497, 499(1:1) 2-20 Η Η &f 35·two FA: 455, N1: 4.40 ( 1H t J=€Hz), 4.73(1K m), 522(1K m), 6.77(1K t J=9Hz), 6.87(2H 4 655(1H, m), 7.10(1H( m), 7.16(1K m), 7.32(2H m), 775(2H 13.17(2H, s) ^128-129°0 2-21 Η Η Η 2-OPh FA435 2-22 Η Η Η Thioo3 FA407 2-23 Η Η Η b· Two M&Ph FA429 2-24 Η Η Η p·二 M&fh FA429 2-S Η Η Η 2-f-Py4 FA420 2-26 Η Η Η TTiop2 FA407 2-2B α Η 办 2 Ffli FA471 2-29 F α Η 30SF-Ph FA505 2-31 Η Η Η SMeOCQPh FA459 232 Η Η Η 3G6^tefh FA:449 2-33 Η Η Η FA433 2-34 FF Η SQ5-F-Ph FA489 2-35 Η Η Η FA470 2-36 Η Η Η 3N {Mel2SQ?Ph 'A508 -52 - (49)1342307 Table 15

\4 H〇OH 寊例编号ΑR4〇, data 2-37 3·5·dimorph 2 not FA455, N1:3.15(1K m), 332(1H, m), 4.64(1K m), 4.79( 14 m), 526(1H m), 6.92(4K m) 7.11(1^UJ=6Hz), 727(1HΛJ=6Ha732(2Km)I7.75|2Hm), 13.18(2Ks), mp:21W190C 238 a5 f publication 4F FA455, N1: 324 (2K m), 4.68 (1H, m), 4.84 (1K t > 6Hz), 5^8[1H, d, > 5Hz), 659pH. m) S.96( 1 K m), 729 (3K m), 7.44(1 H, m), 7.73(2H, m), 13.09(2H s)( rTyx2〇g-2D3°C_ 2-39 You two f^ph SF FA: 455 24) H PA449 2-41 H FA: 433 242 H FA415 243 ' 4asf-Ph Ί H FA453 244 ^F-3CFyPh H FA487 2-45 JCN^h H FA*426 246 3Br4i-Ph H FA497,499(1 :1) 247 3,4·2Ofh H FA469 2-48 Tear three Ffh H FA:455 N1:4.44(1K m), 4.72(141 J=6Hz), 5.18(1K 4 J=4Hz). 6i9(1H m), ZIW m) 7320K m), 7.76f2H, dd, J=3Hz, 6Hz)t 13·19(2Κ s), ^:127-129°0 249 Ph H FA401 2-50 a〇Ph H FA435 2 -51 4*〇Ph H FA435 2-52 2-MfrPh H FA415 2-53 4Mefh 1 H FA:415 2-54 3f-Ph 2-F FA437 2-55 JF-Ph 4f FA437 2-56 2-aSF- PhH H FA453 2-57 2-F-Ph H FA419 2-58 Pan-F-Ph H FA437 N1: 4.42 (1K m), 4.6Θ (1Η t J=6Hz), 5.14(1K d, J=4Hz), 7.10(9H m)( 7.^(2H( m) iai7PH,s), mp:12M3rC 2·5Θ Sf-Ri 2A二F FA455 -53- (50) 1342307 Table 16

Problem· X Data 2-60 Η F 1,1-cPr-z^ FA463 2S1 Η F -CH(COOB)- FA:509 2-62 Η F -CHiOHJCHr FA:467, N1: 297(1H, m), 3.31(2H, m), 4.42(2H, m), 4.50(1K d, J=6Hz) 5.01(1K d, J=€H^, 6.92(^, m), 7.14{3H, m), 731( 3H, m), 773{2H, m) 13.07(2Ks), mp:187-188oC 2-63 Η Η 1,1-cPr--yl FA:445 2-64 Η Η -C(Me)2 - FA :447 2-65 Η Η -CH(Me)- FA433, N1:0.70(^, m), 3.53(^, m), 424(1H, m), 451(1K m), 5.05(1H m), 6.9〇dH,m),7.16(9H, m),7.72(2H, m). 13.06(^,8)^:122-12^0 2-€6 Η Η -CH(CN)- FA444 2-67 Η Η -CH(Ph)-FA:495 2-€8 Η Η -CHfhPr)- ES+:461 2-69 Η Η -CH(MeOCH2)- E&f:463 2-70 Η F -CH(Et) - ES+:465 2-71 Η Η -CH_e)2CH2| - FA:476 2-72 Η Η -CH(cBu)- FA473 2-73 Η F -CH(cHex)- FA519 2-74 Η Η -CH( cPr)- FA459 2-75 2-F Η -CH(Me)- FA451 2-76 Η Η -CH(CF3)- FA487 -54 - (51)1342307

Table 1 7 Example number STR Data 2-19 〇< HO 0H ES+: 437 2-27 HO^ 0H FA455 2-30 FA437 2-77 0ηΚη ES+: 491 2-78 F Η 〇, wide S HO-S OH FA; 451 Example 3-1 A 6 ml portion containing 0.21 g of 2-(1,3-dihydro-2H-benzimidazol-2-yl)-1-[3-(1,2-dihydroxyethyl) Base phenyl]-3-(3-fluorophenyl)propane-1,3-dione and 0.3 g of methyl orthoacetate in THF with 63 mg p-toluenesulfonate p-55- (52) 1342307 steep After mixing, mix at room temperature for about 30 minutes. After evaporating the solvent, the residue was combined with an aqueous solution of sodium bicarbonate, and extracted with EtOAc EtOAc. The resulting residue was purified by hydrazine column chromatography eluting from ethyl acetate-hexane (1:2) to afford 162 mg (68%) of 2-(1,3-dihydro-2H-benzimidazole -2-yl)-1-(3-fluorophenyl)-3-[3-(2-methoxy-2-methyl-1,3-dioxolan-4-yl)phenyl]propanoid a pale yellow foam of -1,3-dione (Example 3.1). In the same manner, the compound shown in Table 18 was obtained. Table 1 8

Example number R; rb Data 3-1 MeO Me FA: 475, N1:1^5PH, s) ( 328(3H, m). 3.41(1H, m), 432(1H, m), 5.07(1Hf m ), 6.92(1H, m) 7.10(5H.m). 7.3(X4H.m\ 7.74(2H.m\ 13.13(2H, s). ^2 MeO H FA461, N1: 3.30(3Hf m), 3.43( 1Ht m), 4.31(1H, m)( 5.05(1H, mX 5.95(1Η, m)f 6.91(1Hf m) 7.09(5H. m). 729(4Η, m). 7.74(2H( m), 13.13 (2H.s). S3 vin H FA: 457 S4 EtO B FA: 503 Example 4-1 - part contains 1.68 g of 2-(1,3-dihydro-2H-benzimidazol-2-yl)- {3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]phenyl}-3·(3-fluorophenyl)propane·1,3-two The ketone 20 ml = methanol solution was mixed with 560 mg of p-toluenesulfonic acid monohydrate, and stirred at room temperature for 18 hours. The mixture was mixed with an appropriate amount of pure water and a saturated aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate. Anhydrous sulfur-56-(53) (53) 1342307 magnesium sulfate was dried. After concentration, the residue formed was purified by silica gel column chromatography eluting with ethylbenzene-ethyl acetate (3:1 -1:3). 640 mg (42%) 2-(1,3-dihydro-2H-benzimidazol-2-yl)-l-{3-[(4R)-2,2-dimethyl-1,3- Dioxol-4-yl]benzene }-3-(3-Fluorophenyl)propane-1,3-dione (Example 4-1) » In this manner, the compound of Example 4-1 1 was obtained by the following method. 140 mg 3-( 2-(1,3-Dihydro-21-benzimidazol-2-yl)-3-{3-[(4 R)-2,2-dimethyl-1,3-dioxolan-4 -yl]-2-fluorophenyl}-3-oxypropenyl)benzonitrile was dissolved in 5 ml of acetic acid-water (4:1) and stirred at 50 ° C for 3 hours. Evaporation of solvent to use Tol The azeotropic treatment was carried out. The residue formed was purified by silica gel column chromatography, and the foamy substance obtained from the chloroform-methanol (1 - : 0 · 9 : 1 ) was recrystallized from ethyl acetate hexane to give 1 0 5 mg (82%) 3-(2-(1,3-dihydro-2}1-benzimidazol-2-yl)-3-{3-[(111)-2,2-di Benzyl]-2-fluorophenyl}-3- oxypropyl)benzonitrile (Examples 4-11). In the same manner, the compounds shown in Tables 19 to 21 were obtained using the corresponding optically active substances derived from the dihydroxy compound synthesized using AD-mix/3. -57- 3 (54) 1342307 Table 1 9

Example R? RSE X RlDl Fee 拽 4-1 Η 3 > FH - Cht - Η - FA: 419 ^: 4.40(^, m), 4.68 (1K t J=6Hz), 5.15(^, d, J=4Hz)· 7.1CX10H, m), 7.73(2H, m), 13.09(2H, s), mp: 190-191°C 4-2 Η -(叫Η — FA:451 4-3 3-FH —CH2~ Η - FA:437 N1:4.66(1 H, m), 4.82(1 H. t J=€Hz), 5.37(1 H, d J=5Hz), 7.14{9Ht m), 7.73(2H , m), 13.08(2H, s), mp: 127-128°C 44 2-FH-CH2—Η—FA:437, N1:3.11(1H, m), 3.31(1H, m), 4.62(1H , m). 4.77(1H, t, J=€Hz), 523(1H, d, J=4Hz), 6.92(2H, m), 6.99(1H_ m), 7·09(3Η, m), 7.19 (1H, m), 7.31(2H, m) 7.75(2Ht m), 13.17(2H, s), mp: 197-1983⁄4 4-5 2-Me 5~F —CH2 Η — FA:451 N12.34 (3K s), 3.50(2K m), 4.95(1 H. m} 6.46(1 K m), 6.73(2H m), 6.98(2Κ m), 729(1 H, m) 7.40C2H, m), 7.53(2^m), 1270(1^ bre), 13.10(1K brs), mp:22&-229°C AS Η 34" H —Cht— Η — FA;419 4-7 2-FHH —CH2 Η — FA: 419 Bu 3-FH-CHt-Η FA: 475 N1O.90 (3K t J=7Hz) t 1.17(4H, m), 1.83(14 m), 229(1H, m), 2.93( 1K m), 3.06(1K m), 4.55-4.63(1 H m ), 4.71 ((1 H, t J=€Hz), 5.00(1 H, m), 67& 6.94(5Ht m), 7.04<1H, m), 7.14(1H, m), 729(2H, cJd, J=3Hz, 9Hz), 7.75(2H, dt, J=3Hz, 9Hz) 13.10(2K s), mp: 132-1333⁄4 4-9 2-f 30 H —CH2_ Η — FA:453 N1:4.63 (1 K m), 478 (1 H, t, J = 6 Hz), 524 (1 H, d ϋ = 4 Ηζ), 7.12 (9H, m), 7.76 (2Ht m), 13.18 (2H, s), mp 139-1403⁄4 Φ10 2-F 3-FH-CH2—F — FA: 465, N1:3.11(1K m), 3.32(1H, m), 4.62(1K m), 4.78(1 H, t J=6H4 523 (1 H, d, J=5Hz), 6·95(3Η, m) 7.1^, mX 7.19(2Η, m), 7.54(1H, m), 7.72-775(^, m), 1322(2H, s), mp: 20&-209°C 4-11 2-f 3CN H-Cht— Η — FA:444 4-12 2-FS^eO H —Chfc— Py3CH2〇oxal K+.562

•58- 3 (55)1342307 Table 20

Example number R« mm 4-13 2-α H 2 her FA449 4-14 3-Me H 2-f FA:433 415 30 H 2-0 E&f:460 ^293(^01),4.76(3⁄4 m), 533(1K m), 7-〇9(6K m), 725(1H m), 733(2K d, Feng 16 2-Me H 2-f FA:433 4-17 2-0 H 4f FA :453 N1:4.66(1K m), 4.81(1H, rri), 534(14 d. J=5H^, 6.77(1H, m). 7.01(3H.m), 7.16(2H m), 732pH, dd , J=3Hz, 6Hz), 7.42[1H, m), 7.75(2H, dd. J=3Hz. 6H^, 1320(2H s) mp:135 137°C 4-18 sa H 4f FA453 N1126(2H m ), 4.67(1H, m), 5^5(1H.m), 6.86(1Κ m), 7.08(1K m), 723(6K m) 7.45(1H m) 13.08(2H,s). 4-19 3f H 2-MeO FA449 4-20 Sf H 2-Me FA: 433 N1: 4.61 (1H, bis), 4.71 (1H, 1 J=6Hz), 5.02(1K bis), &99(7Η, m) 731PH, m), 7.TO(2H γτΑ1^«2Κ^πρ:139·14ΓΟ 4-21 3f H 2-a FA453 N1291(1H, m), 4.78(2H( m), 5.34{1H, m) , 658(6H, m), 724(1H, m), 733(2H, dt J=3Hz, 9m7.77(2H, dt J=3Hz, 9Hz) 132512H, bs), mp: 125-12TC 4-22 SF 4f FA: 455 N1: 4.68 (1K m), 4.85 (1K m), 5.40 (1K d, ^=4H4 6B5(4K m), 7.30(3H, m), 7.45(1H dd, J=2Hz, 7H ^, 7.74βΗ, dd, J=3Hz, 6H^, ΙΙΙΟβΗ, s), mp^47-149°C 4-23 30 H 2-Me ES+: 449 ΝΠ: 231(3K s), 332(1H m), 3.58(1K m), 452(1Η, m), 7IX)(4H m), 7.12(2H,.m)( 723 (1H, m) 738f2H.ni), 751(^^), 1Z70(1Htbis), 13.10(1Kbrs) 4-24 2-0 H 2-f FA453 425 H 2-Me FA:429 N12.18PH, s) ( 226pH, s), 147(2Κ m), 4,85(1Κ m), 6.94(5K m), 7.17(1K m) 736(2K m), 750(2H m), mp: 196-197°C 4-26 3*MeO H 2-f FA449 4-27 HH 2-Me ES+:415

-59- (56) 1342307 Table 21

Case No. ringA RSE R« DATA 4-28 Ph 2-FH 2-f FA:437 4-29 Ph 2-FH 2-Me ES+:433, N12^3(3H, s), 3.46(2H, m) , 4.93(1 H, m), 6.62(1 H, m) 5.82(1H, ml 7.12(5H, m), 7.41(1H, m). 7.52(1K m), 13.10(2H, m' mp:215 -217°C 4-30 Ph 5-F 2-a ES+: 471 N1: Z98(1H, m), 4£1(2H, m), 5.48(1Ht m), 6.87(3H, m), 7.09( 2H( m) 729(3Htm) 7.75i2H, dt J=3Hz, 9Hz), 13J27(2H, brs), mp: 126-1293⁄4 4-31 Ph 40 H ES+:453 4-32 Ph 3-Me H 2- a FA449 N1: 2.15(3Hf s). 2.86(1H, m), 4.75(1H, m)t 4.78(1H, t J=6Hz) 527(1H, m), 6.96(6H, m), 7.19(1H , m), 7.32 (2H, dt, J=3Hz, 9Hz), 7.75{2Ht dt, J=3Hz, 9Hz), 1320(2H, brs) 4-33 Ph 3-F 5-F 2-f FA: 465 SI1: 3.15(1 H, m), 3.32(1 H, m), 4.64(1 K m), 479(1 H, m), 526(1 H, m), B.92(4H, m) t 7.11 (1H, t J=6Hz), 727(1 H, t J=6Hz). 7.32(2H m), 7.75(2H, m), 13.18(2H, s), mp:21&-219eC Winter 34 Pv3 HH 2-F ES+:420 4-35 Ph 4a H 2-a ES+:469 4-36 Ph HH 2-a ES+:435 4-37 Ph 2-f H 2-a FA:453 4-38 Ph SNC H 2-a FA: 460 4-39 Ph HH 2-a ES+: 419 4^40 Ph 3^le H 4-F ES+: 433 441 Ph 3^ r H 4-F ES+: 497,499 (1:1) Example 5 contains 0.11 g of 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazole-2 -yl)-3-{3-[1-hydroxy-2-(methylsulfanyl)ethyl]phenyl}propane-1,3-dione in chloroform solution with 0.13 g of 77% 3-chlorobenzyl acid Mix and stir at room temperature for about 30 minutes. The reaction liquid was mixed with an appropriate amount of aqueous sodium hydrogencarbonate solution, and extracted with EtOAc (EtOAc) EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 1) Solubate to obtain 8 5 mg (71%) 1 - (3 , 5 -difluorophenyl)-2-(1,3- -60 - (57) (57) 1342307 dihydro-2H-phenylene A yellow foam of imidazolium-2-yl)-3·{3-[1-hydroxy-2-(methylsulfonyl)ethyl]phenyl}propane-1,3-dione. ES+: 499. Example 6-1 1 〇ml contains 184 mg of 1-(1,3·dihydro-2H-benzimidazol-2-yl)-1-(3-fluorophenyl)- at -10 °C. A solution of 3-[3-(1.hydroxy-3-ethoxybutyl)phenyl]propane-1,3-dione in ethanol was mixed with sodium borohydride and stirred for 30 minutes. This was mixed with an appropriate amount of a saturated aqueous solution of ammonium chloride and purified water, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After concentration, the residue formed was purified by silica gel column chromatography eluting with hexane-ethyl acetate (1: 1-1:3) to give 110 mg (60%) of 2-(1,3-dihydro- 2H-Benzimidazol-2-yl)-1-[3-(1,3-dihydroxybutyl)phenyl]_3_(3-fluorophenyl)propane-indole, 3-dione (Example 6 -1). The compounds shown in Table 22 were prepared in the same manner.

-61 - (58)1342307 Table 22

Example No. R5" R502 ringB R2 R3 X Data 6-1 F 苯 Benzene-U·Diyl-ΟΗ H -CHzCHiMe)- FA:447 &-2 F 苯Benzene-U3-diyl α H * CH2 FA;437 6-3 -FF Benzene-oxime, 3·diyl oxime Me bond FA: 421 & 4 -FF Benzene-1,3-diyl-OAc H -CH2 · FA; 479 6-5 F -OAc H -ch2 - not purified ^6 F phenyldiyl-N (called H -ch2-FA.464 6-7 F stupid-1,3-diyl-SMe H -ch2-FA: 467 6-8 not F benzene-1> Diki-Nj H -ch2- unpurified 6-9 FH benzene-1>diyl-OH H-CH(OAc)CH(Me)-ES+: 505 Example 7-1 5 ml containing 200 mg 2-(l ,3-dihydro-2H-benzimidazol-2-yl)-1-φ [3-(1,2-dihydroxyethyl)phenyl]-3-(3-fluorophenyl)propane-1 , 3-dione and 53 μl of 2-methylpropionic acid in DMF solution were sequentially added with 88 mg of 1-hydroxybenzotriazole monohydrate, 1 10 mg of WSCHC1 and 70 mg of di-full; aminopyridine; After stirring at room temperature for 18 hours, it was mixed with an appropriate amount of pure water, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After concentrated, the residue was purified by EtOAc EtOAc (2 : 1-0 : 1) Dissolve gets 90 Gram (39%) 2-{3-[2-(1,3-dihydro-2H-benzimidazol-2-yl)-3-(3-fluorophenyl)-3-onepropanate Phenyl-2-phenylethyl-2-methyl ester (Example 7-5) -62 · (59) 1342307 In the same manner, the compound shown in Table 23 was obtained. Table 23 〇S01

Example number R® R1 R2 X Data 7-1 F Η Η -OCOMe FA461 7-2 FF Η -OH -CHINiMeK»]- FA-508 7-3 F Η COMe -OCOMe -CH2- FA503 74 F Η -CQiPr -OOOPr -Ofc-FA559 7-5 F Γ Η .Η -OCOPr -at- FA:489 Example 8 - part 0.35 g of 2-(1,3·dihydro-2H·benzimidazol-2-yl 2 Hydroxyethyl)phenyl]-3-(3-fluorophenyl)propane-1,3-dione was added to φ 10 ml containing 0.14 g of N,N-dimethylglycine hydrochloride, 0.14 g of HOBt In a solution of 0.19 g of WSC hydrochloride and 0.28 ml of TEA in DMF, the mixture was stirred at room temperature for about 12 hours. The reaction liquid was mixed with an appropriate amount of aqueous ammonium chloride solution, extracted with ethyl acetate several times, dried over anhydrous magnesium sulfate and concentrated, and then the residue was purified by column chromatography, from chloroform-methanol (5:1) The lysate gave 0.3 g of a yellow foam. This was dissolved in 15 ml of ethyl acetate, and 0.5 ml of a 4N hydrochloric acid-ethyl acetate solution was added dropwise thereto, and the mixture was stirred at room temperature for about 15 minutes, after which the crystals formed were collected by filtration and dried to give 0.2 g (44). %)(dimethylamino)acetic acid 2--63 - (60) (60) 1342307 {3-[2-(l,3-dihydro-2H-benzimidazol-2-yl)-3- White crystal of (3-fluorophenyl)-3-oxypropanyl]phenyl}-2-hydroxyethyl ester hydrochloride. FA: 504 ° Example 9-1 One part 〇ml containing 104 mg of acetic acid 1·[{3-[2-(1,3-dihydro-2H-benzimidazol-2-yl)-3-( 3-Fluorophenyl)-3-oxypropenyl]phenyl}(hydroxyethyl)]-2-hydroxypropyl ester in THF and 2 ml of methanol solution mixed with 0.62 ml of 1.0 Μ sodium hydroxide And stir for 30 minutes. This was mixed with an appropriate amount of saturated aqueous ammonium chloride solution and purified water, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After concentration, the residue formed was purified by silica gel column chromatography eluting from hexane-ethyl acetate (1: 1-1 '3) to give 35 mg (37%) of 2-(l,3-dihydro). -2H-benzimidazol-2-yl)-l-(3-fluorophenyl)-3-[3-(l,2,3-trihydroxybutyl)phenyl]propane-l,3-di Ketone (Example IX). In the same manner, the compounds listed in Table 24 and Examples 9-5 and 9-6 were obtained. Example 9-5 2·(1,3-Dihydro-2Η-benzimidazol-2-yl)-1-(3-fluorophenyl)-3-[3-(hydroxymethyl)phenyl] Propane-1,3-dione FA: 389 Example 9-6 1-(3,5·Difluorophenyl)-2-(1,3-dihydro-211-benzimidazol-2-yl) -3-[3-(hydroxymethyl)phenyl]propane-1,3-dione FA : 407 -64 - (61)1342307 Table 24

HO* SR2 α: Instance code R*" m B顼R4 X Data 9-1 F 苯 Benzene-1.3·Diyl-OH-CH(OH)CH(Me 卜ES+: 463 9-2 FF Benzene-1&gt Dibasic bond FA: 407 Μ FF Thiop-2,5-diyl-OH —ch2—FA: 443 »4 FF Benzene-U·diyl-OH-CH(COOH)-FA: 481

Example 1 0 Under ice cooling, 0.54 g of sodium periodate was added to 3 ml containing 0.25 g of 2-(1,3-dihydro-2H-benzimidazol-2-yl)-1-{3- [2·(1,2-dihydroxyethyl)-1,3-dioxolan-4-yl]phenyl}-3-(3-fluorophenyl)propane-1,3-dione THF - Aqueous methanol (1 : 1 : 1), stirred at room temperature for about 30 minutes. The reaction liquid was mixed with an appropriate amount of saturated brine, and extracted with ethyl acetate. This material was dissolved in 5 ml of dichloromethane, and 60 μl of morphine and 0.3 ml of acetic acid were sequentially added, followed by the addition of 0.22 g of sodium triacetate hydride under ice cooling, and the mixture was stirred at room temperature for about 30 minutes. . After evaporating the solvent, the residue was combined with aq. sodium hydrogen sulfate, and extracted with ethyl acetate. The resulting residue was purified by silica gel column chromatography to obtain 16 g (60%) of 2-(1'3·dihydro-2H-benzimidazol-2-ylfluorophenyl) from ethyl acetate. -{3-[2-(morpholine-4-ylmethyl)-oxime, 3·dioxolan-4-yl]phenyl}propane-oxime, 3-diketone yellow-65- (62 ) 1342307 color foam. FA: 530. Example 1 1 A portion of 0.33 ml of 2-bromopyridine was dissolved in 3 ml of THF, and the solution was cooled to -78 ° C, mixed with 2.2 ml of n-butyllithium, and then stirred at the same temperature for 30 minutes. This solution was poured at -78 ° C by 3-[2·(1,3-dihydro-2 Η-benzoimidazol-2-yl)-3-(3-fluorophenyl)-3- A solution prepared by dissolving oxypropenyl]benzaldehyde in 10 ml of THF. The material was slowly warmed to room temperature and mixed with 50 ml of a saturated aqueous solution of ammonium chloride. This was extracted with ethyl acetate, dried over sodium sulfate and then concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol = 1:1: 0 to 90:1). The resulting reddish brown solid formed a salt with 4N EtOAc /EtOAc (EtOAc) (EtOAc) -Fluorophenyl)-3-{3-[hydroxy(pyridin-2-yl)methyl]phenyl}propane-1,3-dione hydrochloride (Example 11-1). FA: 466.

In the same manner, 2-(1,3-dihydro-2H-benzimidazolyl-2-yl)-1-(3-fluorophenyl)·3-{3-[hydroxy(1·methyl) was obtained. -1H-imidazol-2-yl)methyl]phenyl}propane-1,3-dione hydrochloride (Example 11-2). FA: 469. Example 1 2 parts by weight of 2 ml containing 100 mg of 1·[3-(chloromethyl)phenyl]-3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H- A solution of benzoimidazol-2-ylpropane-1,3·dione in DMSO was mixed with 35 mg of potassium acetate and stirred at room temperature for about 2 days. The reaction liquid is mixed with an appropriate amount of a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate-66-(63) 1342307 several times, dried over anhydrous magnesium sulfate and concentrated, and then the residue formed is purified by a silica gel column chromatography. Ethyl acetate-hexane (1:2) was dissolved to give 90 mg of yellow oil. This crystallized from a small amount of ethyl acetate-hexane (1:3) at a low temperature to give 68 mg (64%) of 3-[3-(chloromethyl)phenyl]-3-(3,5) Yellow crystal of -difluorophenyl)-2-(1,3-dihydro-2H.benzamidazol-2-yl). FA: 449. _ Example 1 3 1-(3,5-Difluorophenyl)-2-(1,3-dihydro-2^1-benzimidazol-2-yl)-3-[3-(1, The isolation of 2-dihydroxyethyl)phenyl]propane-1,3-dione is carried out in the usual manner using a chelating column CHIRALCEL® DH (trademark, Daicel Chemical Industries) and a leaching agent: hexane/ethanol 3: 1 proceed. Obtaining the isomer 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-yl)-3-{3- with a shorter residence time [(lS)-l,2-Dihydroxyethyl]phenyl}propane-1,3-dione (Example 13-1). FA: 43 7. Obtaining the isomer 1-(3,5-difluorophenyl)-2-(1,3-dihydro-211-benzimidazol-2-yl)-3-{3 with a longer retention time of 0 -[(111)-1,2-dihydroxyethyl]phenyl}propane-1,3-dione (Example 13-2). FA: 437,

Nl : 3.2 7(2H,m) > 4 · 4 2 (1 Η,m),4 ' 7 1 (1 Η,t,J = 6 Η z), 5.17(1H,d - J = 4Hz), 6.91 (3H, m), 7.14 (3H, m), 7.30 (3H, m), 7.74 (2H, m), 13.11 (2H, s) 'mp: 189-1 90 °C Example 13-1 [cr ]d+21.3°(c 0.356 eOH) -67- (64) 1342307 Example 13-2 [/3 ]D -21.2 ° (c 0.367 eOH) Example 1 4 One 568 mg l-[3-(2 -azido-1-hydroxyethyl)phenyl]-3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-yl)propane - 1.3-Dione and 120 mg of 10% palladium-carbon were added to 50 ml of ethyl acetate, and stirred under a hydrogen atmosphere at room temperature for 8.5 hours under a hydrogen atmosphere. This material was filtered through calcium ore, concentrated, and mixed with diethyl ether, and then extracted with water. By concentrating the aqueous layer, 2500 mg (47%) of 1-[3-(2-amino-1-hydroxyethyl)phenyl-p-3-(3,5-difluorophenyl)-2- Yellow solid of (l,3-dihydro-2H-benzimidazol-2-yl)propane-1.3-dione (Example 14-1). FA: 436. In the same manner, the following compounds were obtained. Example 14-2 2-(1,3-dihydro-2H-benzimidazol-2-yl)-1-[3-(2-

Ethyl-1,3-dioxolan-4-yl)phenyl]-3-(3-fluorophenyl)propane-1,3-dione FA: 4 5 9 Example 14-3 1-( 3,5-difluorophenyl)-3-{3-[(lR)-l,2-dihydroxyethyl]-2-fluorophenyl}-2-(5-hydroxy-1,3-dihydrol - 2H-ibenzimidazol-2-yl)propane-1,3-dione FA: 471 Example 1 5 137 mg of 1-[3-(2-amino-1-hydroxyethyl)phenyl ]-3-(3,5-Difluorophenyl)-2-(l,3-dihydro-2H.benzamidazol-2-yl)propane-l,3-di-68-(65)1342307 The ketone was dissolved in 10 mL of pyridine and 35 mg of acetic anhydride was added under ice cooling. After stirring at room temperature for 2.5 hours, the reaction liquid was mixed with an appropriate aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated, and then the residue formed was purified by gel column chromatography from chloroform. · Methanol (30: 1) dissolvate to obtain 120 mg (80%) of N-{3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-phenylene) Yellow foam of imidazol-2-yl)-3-oxypropenyl]phenyl}. 2-hydroxyethyl)acetamide (Example 5-1.1). FA: 478 制 was obtained in the same manner = the following compound ° Example 15-2 Ethyl carbonate 2-{3-[2-(1,3-dihydro-2H-benzoimidazole-2-yl)·3 -(3-phenylphenyl)·3·oxypropanyl]phenyl}-2-ylacetic acid FA: 491

Example 15-3 2-{3-[2-(1,3-Dihydro-2Η-benzoimidazol-2-ylfluorophenyl)·3·oxypropyl]phenyl}-acetate 2-Hydroxyethyl ester FA: 46 1 Example 15-4 (Dimethylamino)acetic acid 2-(ethyloxy)-2-{3-[2-(l,3-dihydro-2H- sub Benzomidino-2-yl)-3-(3-fluorophenyl)-3.oxypropanyl]phenyl}-ethyl ester FA = 546 Example 1 6 A 300 mg 2-0, 3-Dihydro-2H-benzimidazol-2-yl)-1-[3--69-(66)1342307 (1,2-dihydroxyethyl)phenyl]-3·(3·fluorobenzene Propyl-i,3-dione and 200 mg of 1,1'-carbonyldiimidazole were dissolved in 7 ml of To® and stirred at 80 ° C for 12 hours. After the reaction liquid was concentrated, the residue formed was purified by silica gel column chromatography eluted from chloroform-methanol (1 〇: 1) to give 30 mg (9%) of 2-(1,3-dihydro-2H- Benzimidazol-2-yl)-1-(3-fluorophenyl)3·[3-(2·oxy)1,3-1,3-dioxolan-4-yl)phenyl]-3-propane a yellow solid of -1,3-diketone. ES+ : 445 °

Example 1 7 According to the method of the above Example 1, 1-(3,5-difluorophenyl)-2-(1,3·dihydro-2H-benzimidazol-2-yl)-3- [3-(2,2-Dimethyl-1,3-dioxolan-4-yl)phenyl]-propane-1,3-dione. ES+: 491» Example 1 8

One part of 0.12 g of 2-[bis(methylsulfanyl)methyl]-l-[3-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl) 2-fluorophenyl]-3-pyridin-3-yl-propane-1,3-dione and 36 mg of 1,2-phenylenediamine were dissolved in 8 ml of ethanol and heated under reflux for 3 hours. After the reaction liquid was concentrated, the residue formed was purified by silica gel column chromatography eluting from ethyl acetate-hexane (3:1) to give 2-(1,3-dihydro-2H-benzimidazole- 2-yl)-1-[3-(2,2-dimethyl·1,3-dioxolan-4-yl)-2-fluorophenyl]-3-pyridin-3-yl-propane- ], a yellow solid of 3 · diketone. FA: 460. Test Example 1. Test for GnRH Receptor Antagonism-70-(67)1342307 GnRH Receptor Antagonism of Compound of the Present Invention l. GnRH Receptor Antagonism Test Method described on page 56 125I-D-Trp6-LHRH pair The results of the human GnRH receptor junction are listed in Table 25. Test Example 2. Measurement of compound by in vitro binding assay] The compounds to be tested were each dissolved or suspended in a (M C) solution and passed through a Wister male mouse (SLC Japan) at a dose of 1 mg/kg. The drug was administered for 2 hours to obtain serum. Each serum sample was diluted with the same volume of methanol, optionally with an assay buffer, and then the inhibition ratio of 12 51 - D - T r p 6 - L H R Η was determined by virgin. The blood concentration (# Μ) of each compound was calculated for the correction ratio of the individual preparation of the concentration and the inhibition of the binding. The results are shown in Table 25. I is evaluated according to the patent reference 駚1, which calculates the concentration of 50% inhibition. Blood concentration> 0.5% methylcellulose mouth was administered after 9 weeks of large blood samples were collected and mixed to remove proteins] in the same manner as in Test Example 1, with self-binding inhibition -71 - (68) 1342307 Table 25 Test compound Test Example 1 GnRH receptor antagonist (8) IC5 〇 (nM) Test Example 2 Blood 'concentration concentration (B) 2 hours 値 _ (b) / (A) * Ex 2-3 0.082 0.71 Ex 2-4 0.17 1.31 Ex 2-5 0.10 0.82 6?2 Ex 2-7 0.19 1.65 Ex 2-12 0.15 0.92 Ex 2-20 0.20 1.14 sTj ~~~ Ex 2-48 0.22 2.16 Ex 2-50 0.12 0.88 _ TTi Ex 4-1 0.093 1.36 ___^476 Ex 4-4 0.10 1.04 Ex 4-5 0.12 3.74 _3ΓΓ2 Ex 4-8 0.081 1.79 _227ΐ~~~ Ex 4-15 0.076 1.44 Ex 4-21 0.24 2.17 Ex 4-22 0.13 2.17 Ex 4-23 "0·18 1*11 Ex 4-25 0.14 1.39 Hrr- Ex 4-29 0.19 6.44 Ex 4-30 0.10 1.5 __T5?0 Ex 4-32 0.12 0.67 ^7T- Ex 4-33 0.12 1.59 iT7i Comparative Compound 1 0.95 1*49 ΐχτ- Control Compound 2 0.97 1.29 Π - Control Compound 3 0.19 0*04 ® Control Compound 1 : Example 4 described in Patent Reference 1 0 Control Compound 2: Patent Reference Example 2 described above 5 1 Comparative compound 3: Example 2 described in Patent Reference 1 3 9 shows the ratio of blood compound concentration (B) to GnRH receptor antagonist (A). GnRH receptor is considered The strength of the antagonist in vivo is related to the gastric and gastric receptor inhibitory activity and the blood drug concentration, and has a larger ratio of the blood drug-72-(69) (69) 1342307 concentration to the in vitro receptor inhibitory activity. The compound has a strong pharmacological effect in vivo. Since the compound of the present invention has a GnRH receptor antagonist similar to or greater than the compound disclosed in Patent Reference 1, the ratio of blood concentration to receptor inhibitory activity (B) / (A) Further improvement, confirming the efficacy that can be expected to perform better in vivo. For example, in Table 25, when the blood concentration is high, the IC50 of the antagonistic activity is small, the drug effect is large, and the drug is strong in vivo. Test Example 3. Antagonistic Test for GnRH-Induced Blood Ketone Increase Reaction The in vivo GnRH receptor antagonist of the compound of the present invention is based on the "Phase 57 of the Patent Reference 1" 2. The GnRH-induced blood testosterone-increased response Evaluation of the method described in the Antagonistic Test. The compounds to be tested were each suspended in an aqueous solution of 0.5% methylcellulose (MC) and administered orally at a dose of 1 mg/kg 2 or 4 hours before administration of GnRH. The compounds of the invention have good antagonistic properties. Test Example 4. (Evaluation of drug interaction) (1) Calculation of inhibition test U inhibitory activity I) Using 95 well plate 'at 100 ° mM phosphate containing 〇.1 mM EDTA and 1 mM NADPH at 37 ° C In the buffer, the substrate (midazolam), the test compound, and human liver microsomes (〇1 mg protein/ml) were incubated for 20 minutes. Thereafter, the reaction was terminated by adding an aqueous solution containing 80% acetonitrile. Thereafter, each sample was analyzed by HP LC' using the formula -73-(70) (70) 1342307 to calculate the inhibitory activity I. As a result of this test, for example, the compound of Table 26 shows superior effects to the compound of Example 251 described in Patent Reference 1. Inhibitory activity ΚχρίΟΟ-ν,.,/νο.,χίοο V 1": in inhibition test I, the metabolic rate in the presence of a test compound of known concentration V〇.i: in inhibition test I, the substrate Metabolic rate in the absence of a test compound of known concentration

-74- 1342307 (71 Table 26)

Objects 345715801389 3 4789367890406782548 428135905 fit. - I 111222 2 233333444445555556622-9121222231 2 222----------------------------4- ------- - Ad -\J 22222222222222222222222222444444444444/1 /1 /1 Illumination 1 nD/ By pair CYP3 A4 inhibitory activity 1 (%) 2 6 18 17 1 5 -5 14 -9 -4 0 -2 -9 4 4 -2 -10 1 3 -1 2 -10 -5 10 9 -1 -6 -8 9 4 40 53 58 -75- (72) (72) 1342307 (2) Inhibition test II (inhibition Calculation of Activity II) Using a 95-well plate, the test compound and human liver were incubated at 37 ° C in a total volume of 145 μl of 100 mM phosphate buffer (pH = 7.4) containing mM EDTA and 1 mM NADPH. Microsomes (〇.mg mg protein/ml) lasted for 30 minutes. Thereafter, midazolam as a substrate was added and incubated at 37 ° C for 20 minutes. After the incubation, the reaction was terminated by the addition of an aqueous solution containing 80% acetonitrile. Thereafter, each sample was analyzed by HPLC to calculate the inhibitory activity Π. Inhibitory activity 11 (%) = 1 〇〇 - \ ^ 111 / 乂 (). 11 / (1 〇〇 - inhibitory activity 1) >< 10 (^100 Vkh: in inhibition test II, subject to Metabolic rate in the presence of a test compound of known concentration V0 II: in the inhibition test II, the metabolic rate in the absence of a test compound of known concentration, such as Examples 2-4, Examples 4- 1 The compounds of Examples 4-4, 4-5, 4-21, 4-22, 4-25, 4-29 and 4-30 are shown in the patent reference 1 Example 40, Example 251 and Example 23 9 The superior effect of the compound. Test Example 5 - Metabolic stability test in human liver microsomes Using a test tube containing O.lmM EDTA and 1 mM NADPH at 37 ° C In a 100 mM phosphate buffer (pH = 7.4), test the -76-(73) (73) 1342307 compound and human liver microsomes (0.2 mg protein/ml) for 15 minutes. After incubation, add The reaction was terminated by an aqueous solution containing 80% acetonitrile. After that, each sample was analyzed by HP LC, and the in vitro clearance rate was calculated using the integral map. For example, in comparison with Example 40, Example 251 and Example 23 9 described in Patent Reference 1, Example 2-4, Example 4-1, Example 4-4, and Example 4 -5, Examples 4-21, Examples 4 - 2 2. Examples 4 - 2 5, Examples 4 - 29 and Examples 4 - 3 0 show superior metabolic stability in human liver, It is less likely to have an initial pass effect. As described above, in addition to potent GnRH receptor antagonism, the compounds of the present invention also exhibit superior blood mobility when administered orally. Therefore, the compounds of the present invention are useful for treating gonadal hormone dependence. Diseases, especially diseases associated with GnRH, such as prostate cancer, breast cancer, endometriosis, uterine leiomyoma, benign prostatic hypertrophy, and the like. Accordingly, the present invention also provides a pharmaceutical composition comprising as an active a propane-1,3-dione compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; preferably a pharmaceutical composition of a GnRH receptor antagonist Matter: Better pharmaceutical composition The GnRH receptor antagonist is an agent for treating a disease associated with GnRH, such as prostate cancer, breast cancer, endometriosis, uterine leiomyoma, benign prostatic hypertrophy, and the like. Moreover, the present invention provides A method for treating a patient suffering from a disease associated with GnRH, comprising administering to a patient an effective amount of a propane-1,3-dione compound represented by the above formula (I) or a pharmaceutically acceptable -77- (74) (74) 1342307 salt; preferably a method for treating a disease associated with GnRH receptor, wherein the disease associated with GnRH is prostate cancer 'breast cancer, endometriosis, uterine leiomyoma, benign Prostatic hypertrophy and its class. Further, the present invention provides the use of the propane-1,3-dione compound represented by the above formula (I) or a salt thereof for the treatment of a disease associated with GnRH, and propane-1,3 represented by the above formula (1) Use of a diketone compound or a salt thereof for the manufacture of a medicament for the treatment of a disease associated with GnRH.

-78 -

Claims (1)

1342307 Announcement of the first year of the year Η Ώ repair No. 0941 18378 Patent application Chinese patent application scope revision of the Republic of China 100 years February rev. 10, the scope of application patent 1 · a propane represented by the general formula (1)丨, 3_dione derivative or its pharmaceutically acceptable salt, ~ (I) The symbols in the formula are as follows: Ring: 1 to 3 substituents (wherein the substituent is a halogen 'CN', a CrQ alkyl group substituted by _, a 〇_Cl_C6 alkyl group, _c〇 Benzene substituted with _〇-Ci_cag or amino), may have 1 to 3 substituents (wherein the substituent is halogen, CN, Cl_C6 alkyl which may be substituted by halogen, _〇_C|_c6, - CO-0-Ci-C6 alkyl or amine) substituted pyridine, or thiophene ring, ring B: benzene or thiophene ring, R1: hydrazine or -CO-CrQ alkyl, R2: Η, -O-R5, - N(R6)r7, -n3, -scCOm-Ci-Cealkyl-S(0)mN(R6)R7, halogen, pyridyl or may have 1 or 2 substituents (wherein the substituent is C^) -C: 6 yard base) substituted for the sulfhydryl group, or R1 and R2 together with the X linked to R1 and the X connected to R2 form -〇_c(r8)(r9)-o-ch2-, R8 and R9: may be the same or different from each other, and each is H, C|-C6 alkyl, Ci-1342307 C6, or - 0-C|-C6, R5: Η, C, -C6 alkyl, _c〇-C|_ca substituted by 1 or 2 substituents (wherein the substituent is an amine group or a mono- or di-C"C6 alkylamino group), or may have 1 or 2 substituents (which should be taken The substituent is an amine group or a mono- or di-Ci-C6 alkylamino group substituted with a -CO-O-Ke alkyl group, and R6 and R7: may be the same or different from each other, and each is a hydrazine, a Cl_C6 group, or -CO-Ci-C6院基' m : 0, 1 or 2, R3 : H—Ci-Ce alkyl, RW and RU2 : may be the same or different from each other, and each 舄η, 齿素0 0 •Ci-C6 yard base, or Ci-C6 institute Base, X: bonded, may have 1 or 2 substituents (wherein the substituent is 〇H, c〇〇H, -C〇-〇-Cl-C6 alkyl, halogen, CN, phenyl, 〇CiC6 Alkyl, -〇-C〇-Cl-C6, amino-mono- or di-, Cl-C6-based amine , -C〇-NH2, -CO-mono- or di-Cl_C6-based amine group or C3_C6 ring-based group) substituted Ci-C6-extension base, or C3-C6-cyclononyl group, Rl01, Rl02, can be mutually _0_C|_C6 ribyl groups which are the same or different and each of which is H, halogen, OH or which may be substituted with pyridyl group. 2. The propylene compound according to item 1 of the patent application _丨, 3, ketone derivative is pharmaceutically acceptable a salt, wherein ring A is a benzene ring which may be substituted by halogen or ^6 alkyl group, ring B is a benzene ring, R is H'R2 (10), and H, and oxime may be 1 or 2 substituents (wherein The substituent is 〇Η, C, -C 6 alkyl, halogen CN phenyl, CO-CrCe alkyl, amine, mono- or di-Ci_c C〇〇H ' -C0-0 C 1 - C 6 alkane a C 1 - C 6 extension substituted with a -0 6 alkylamino group, -CO 2 - 1342307 NH2, -CO-mono- or di-c,-c6 alkylamino or c3-c6 cycloalkyl) Court base. 3. A propane-1,3-dione derivative or a pharmaceutically acceptable salt thereof as claimed in claim 2, wherein X is 1 or 2 substituents (wherein the substituent is 〇H, COOH , -CO-OC^Ce alkyl, halogen, CN, phenyl, -0-C丨-C6 alkyl, -〇-C〇-Ci-C6 alkyl, amine, mono- or di-CMC6 alkyl Amino group, -co-nh2, -CO-mono- or di-κ6 alkylamino group or c3-c6 cycloalkyl) substituted methyl group. A propane-1,3-dione derivative represented by the formula (la) or a pharmaceutically acceptable salt thereof, The symbols in the formula are as follows: R8 <n ' r8〇2 and r8〇3 : may be the same or different from each other, and each is η, halogen or alkyl, R4 (n and R4D4 : may be identical or different from each other, and Each is H, halogen or C i -C 6 alkyl; and Ri<n, RlQ2, RlG3 and Ri 〇4: may be the same or different from each other, and each is fluorene, halogen, hydrazine H, or may be pyridyl Substituted -〇_Cl-C6 alkyl. 5-propane-1,3-dione derivative selected from the group consisting of: 2-(1,3-dihydro-2H-benzoindole-2 -yl)-1-[3-(1,2-dipyridyl 1342307 ethyl)phenyl]-3-(3,4,5-trifluorophenyl)propane-1,3-dione; 1- {2-butyl-3-[(lR)-l,2-dihydroxyethylindolyl}-2-(1,3-dihydro-2H-benzimidazol-2-yl)-3- (3-fluorophenyl)propane-1,3-dione; 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2^benzimidazol-2-yl) -3-[5-( 1,2-dihydroxyethyl)-2-fluorophenyl]propane-1,3-dione; 1-(3,5-difluorophenyl)-2-(1, 3-Dihydro-21--benzimidazol-2-yl)-3-{3-[(lR)-l,2-dihydroxyethyl]-2-methylphenyl}propane-1,3 -dione; 2-(1,3-dihydro-2H-benzimidazole-2-yl)-l- {3-[(lR)-l,2-dihydroxyethyl]-2.methylphenyl}-3-(2-fluorophenyl)propane-1,3-dione; 2-(1,3 -dihydro-2H-benzimidazole-2-yl)-1-[3-(1,2-dihydroxyethyl)phenyl]-3-(2,3,5-trifluorophenyl)propane -1,3-dione; 2-(1,3-dihydro-2H-benzimidazol-2-yl)-l-{3-[(lR)-l,2-dihydroxyethyl]- 2-methylphenyl}-3-(3-methylphenyl)propane-1,3-dione; 1-{2-chloro-3-([lR)-l,2-dihydroxyethyl] Phenyl}-2-(1,3-dihydro-2H-benzimidazol-2-yl)-3-(3-fluorophenyl)propane-1,3-dione; 2- (1,3 -dihydro-2H-benzimidazol-2-yl)-l-{3-[(lR)-l,2-dihydroxyethyl]phenyl}-3-(3-fluorophenyl)propane- 1,3-diketone; 1-(3,5-difluorophenyl)-2-(1,3-dihydro-21"1-benzimidazol-2-yl)- 3-[3-( 1,2-dihydroxyethyl)-2-fluorophenyl]propane-1,3-dione; 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2 H - benzoimidazol-2-yl)-3-[3-(1,2-dihydroxyethyl)-4-fluorophenyl]propane-1,3-dione; 1- {2-chloro-3 -[(lR)-l,2-dihydroxyethyl]phenyl}-3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazole-2 -base Propane-1,3-dione; 2-(indolyl, 3-dihydro-2H-benzimidazol-2-yl)-bu {3-[(lR)-l,2-di 1344307 hydroxyethyl -2 -fluorophenyl}-3-(3.fluorophenyl)propane-i,3-dione; and 1-{2-chlorod-KlR)-1,2-dihydroxyethyl]phenyl }-3-(3·Chlorophenyl)-2-(1,3-dihydro-2H-benzimidazole-2·yl)propane-indole, 3-dione; or a pharmaceutically acceptable salt thereof ° 6 - a propane ·], 3-dione derivative or a pharmaceutically acceptable salt thereof represented by the formula (lb) The symbols in the formula are as follows: R8 and R9: may be the same or different from each other, and each is Η, Κ6 alkyl, alkenyl or -Ο-Κδ alkyl; Rs(n, R8〇2 and R8<n · They are the same or different from each other, and each is η, halogen or C^C6 alkyl, R4〇3 and r4〇4: may be the same or different from each other, and each is H, halogen or C | - C 6 yard: and Rl (n, rIQ2, R1〇3, and Rie4: may be the same or different from each other, and each is fluorene, halogen, OH, or -0-(:,-(:6 alkyl) which may be substituted with a pyridyl group. A propane-1,3·dione derivative or a pharmaceutically acceptable salt thereof according to claim 6 wherein R8QI, R8()2 and r8()3 are the same or different from each other, and each is Η Or _. 8. A propane-1,3 -dione derivative' is selected from the group consisting of: 2-(1,3 -dihydro-2 Η -benzimidazol-2-yl)-1-(3) -fluorophenyl)·3-[3- -5- 1342307 (2-carbyl-I,3-dioxolan-4-yl)phenyl]propane-oxime, 3-dione: and 2- (1>3-dihydro-214-bendimidazol-2-yl)-1-(3-fluorophenyl)-3-[3-(2-methoxy-2-methyl-1,3 -dioxolan-4-yl)phenyl]propanoid-indole, 3-dione; or its pharmaceutical use A salt to be accepted. A pharmaceutical composition comprising, as an active ingredient, a propane-1,3-dione compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, as in the first aspect of the patent application. And a pharmaceutically acceptable carrier. 1 0. The pharmaceutical composition of claim 9 is a GnRH receptor antagonist. Π The pharmaceutical composition of claim 0, It is a GnRH receptor antagonist for the treatment of prostate cancer, breast cancer, endometriosis, uterine leiomyoma or benign prostatic hyperplasia. 12··. Propane-1,3-dione derivatives' selection From: 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2^benzimidazol-2-yl)-3-{3-[(lR)-l,2 -dihydroxyethyl]-2-methylphenyl}propane-1,3-dione; 2-(1,3-dihydro-2H-benzoimidazol-2-ylhydroxyethyl]-2 -methylphenyl}-3-(2-difluorophenyl)propane-U3-dione; 2-(1,3-dihydro-2H-benzimidazol-2-yl=hydroxyethyl]- 2-methylphenyl}-3-(3-methylphenyl)propane·1,3-dione; 1-(3,5-difluorophenyl)-2-(1,3-dihydro- 2 H-benzimidazol-2-yl)-3-[3 -(1,2-dihydroxyethyl)·4-fluorophenyl]propane-1,3-dione; and 2-(1,3-dihydro-2Η-benzimidazol-2-yl hl- U-KiRri,]-dihydroxyethyl]-2-fluorophenyl)-3-(3-fluorophenyl)propane-1,3-dione; or a pharmaceutically acceptable salt thereof. -6-